CARDIOLOGY RESEARCH AND CLINICAL DEVELOPMENTS

CONGENITAL HEART DISEASES

AN UPDATED APPROACH TO SOMEIMPORTANT ISSUES

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CARDIOLOGY RESEARCH AND CLINICAL DEVELOPMENTS

CONGENITAL HEART DISEASES

AN UPDATED APPROACH TO SOMEIMPORTANT ISSUES

RAL CAYR, M.D., PH.D.

AND

JOS MILEI, M.D., PH.D.

EDITORS

New York

Copyright 2014 by Nova Science Publishers, Inc.

All rights reserved. No part of this book may be reproduced, stored in a retrieval system ortransmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanicalphotocopying, recording or otherwise without the written permission of the Publisher.For permission to use material from this book please contact us:Telephone 631-231-7269; Fax 631-231-8175Web Site: http://www.novapublishers.comNOTICE TO THE READERThe Publisher has taken reasonable care in the preparation of this book, but makes no expressed orimplied warranty of any kind and assumes no responsibility for any errors or omissions. Noliability is assumed for incidental or consequential damages in connection with or arising out ofinformation contained in this book. The Publisher shall not be liable for any special,consequential, or exemplary damages resulting, in whole or in part, from the readers use of, orreliance upon, this material. Any parts of this book based on government reports are so indicatedand copyright is claimed for those parts to the extent applicable to compilations of such works.Independent verification should be sought for any data, advice or recommendations contained inthis book. In addition, no responsibility is assumed by the publisher for any injury and/or damageto persons or property arising from any methods, products, instructions, ideas or otherwisecontained in this publication.This publication is designed to provide accurate and authoritative information with regard to thesubject matter covered herein. It is sold with the clear understanding that the Publisher is notengaged in rendering legal or any other professional services. If legal or any other expertassistance is required, the services of a competent person should be sought. FROM ADECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THEAMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS.Additional color graphics may be available in the e-book version of this book.

Hybrid Procedures for Congenital Heart Disease:

Strategy for Biventricular Outflow Tract Reconstruction

for the Transposition of the Great Arteries with VentricularSeptal Defect and Left Ventricle Outflow Tract Obstruction:Rastelli Procedure and the Newer AorticTranslocation TechniquesClaudia Natalia Villalba, Mariela Mouratianand Horacio A. Capelli

Chapter 13

Adult Congenital Heart Disease: Problems and Perspectives

Horacio Capelli and Mariela Mouratian

Chapter 14

Management of Cardiac Emergencies in Children

Editors Contact Information

305

Index

307

PrefaceCongenital heart diseases are of the utmost importance in modern cardiology. This is abook that deals with essential matters which are developed by experienced researchers in theirrespective fields. An updated approach to these issues was largely sought after. The authorsshare their own papers and experience with the enthusiastic professionals reading their workall throughout the chapters in an easy-to-read format.Modern medical practice demands continuous research on specific topics. Thereafter, thisbook is devoted to the development of the coronary arteries facing the fact that coronaryartery disease is the most common cause of mortality in the developed world. The the role ofthe estrogen receptor and transforming growth factors in coronary intimal hyperplasia andthorough descriptions of new diagnostic techniques in congenital heart diseases are alsodisplayed (severe congenital heart defects are generally diagnosed during pregnancy or soonafter birth while less severe defects often are not diagnosed until children are older).Accordingly, complex malformations of the heart, fetal arrhythmias and pulmonaryhypertension are also included.In as much as other specific subjects are relevant as well, topics like an etiologicaloverview of intrauterine ductus arteriosus constriction, restrictive cardiomyopathy in childrenor hybrid procedures for congenital heart disease, namely palliation of hypoplastic left heartsyndrome, closure of muscular ventricular septal defect and stenting of branch pulmonaryarteries are developed as well.Last but not least, the long-term outcomes of congenital heart diseases, includingmedical, interventional and emergency treatments, are examined.Chapter 1 The embryological development of the coronary arteries in humans is stillcontroversial. It is unclear whether there is a dual process of angiogenesis and vasculogenesisor a single process of vasculogenesis. Objective: This chapter examines the development ofthe coronary arteries in human embryos within the context of recent experimental findings.Methods: Of 131 human embryos and fetuses, 22 between stages XIII (272 days) and XVIII(481 day) were studied. Results: Islands of angioblastic cells appeared in stage XIII. Bystage XV two distinct subepicardial vascular networks were seen which connected to theaorta by stages XVII-XVIII. Endothelial indentations were seen in stages XV and XVI onlyin the region of the aorta just above the developing aortic sigmoid valves; no directconnections could be confirmed to the subepicardial vascular network therefore we cannotconclude that these are involved in the formation of the proximal coronary trunks as has beenpreviously proposed. Compaction of the ventricular myocardium began in stage XV at the

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base of the heart and extended towards the apex. Conclusion: The coronary arteries in thehuman embryo seem to develop through vasculogenesis with the appearance of islands ofangioblastic cells which coalesced to form two subepicardial capillary networks; these wereclearly distinct by stage XV. The connection of both vascular networks via coronary channelsto the aorta was invariably present by stage XVIII.Chapter 2 Congenital heart defects (CHD) and/ or their repair process lead to anincreased risk for adult cardiovascular disease compared with the general population.Intimal hyperplasia is a pre-atherosclerotic lesion that may be produced as a consequenceof the activation of transforming growth factor beta-1 (TGF-1) pathway or ER inhibition.This chapter deals with the authors recent findings in this regard and comments in theirlatest results in connection with relevant reports from other authors.The authors examined the coronary arteries from a pediatric population with CHD andevaluated the possible relationship between the frequency of intimal hyperplasia and themagnitude of TGF-1 in order to enlighten the possible role of TGF-1 in the genesis of theselesions. The coronary arteries of 10 control patients and 98 CHD patients (54% cyanotic type,32% surgically repaired) were stained and assessed for the presence and degree of intimalthickening. The expression of TGF-1 and ER was determined by immunohistochemicalexamination.The frequency of coronary intimal hyperplasia did not depend on the group, i.e.: cyanoticCHD group (66%) and non-cyanotic CHD group (64%). However, the frequency of coronaryintimal hyperplasia was higher in patients with surgically repaired CHD than in patientswithout surgical intervention (80% vs. 47% respectively, p=0.0002).The degree of positive immunostaining for TGF-1 or ER did not depend on the group.i.e.: cyanotic and non-cyanotic type. On the other hand, examination of the intimal layershowed that TGF-1 expression was higher and expression of ER was smaller in patientswith surgically repaired CHD compared with those without surgery.The relationship between the frequency of intimal hyperplasia and the expression ofTGF-1 and ER in arteries from 98 pediatric patients with congenital heart defects indicatedthat: 1) intimal hyperplasia was a common finding in the coronary tree of these patients, 2)both TGF-1 and ER seemed to play a major role in this phenomenon and 3) surgicalcorrection of CHD was associated with further coronary vascular remodeling.Chapter 3 New diagnostic techniques can help to understand the myocardial function incongenital heart disease. Echocardiography is a reliable, noninvasive tool to evaluate heartstructure and contractile function of the left and right ventricle in children and adults. 2Dcolor Doppler imaging of the myocardium enables rapid qualitative assessment of walldynamics, providing a good spatial resolution to differentiate between velocity profiles ofsubendocardial and subepicardial layers, and allows simultaneous analysis of variousmyocardial regions. Tissue Doppler velocity imaging (TDI) offers a different approach, as itdoes not rely on geometric assumptions. Possibly, the best option for the evaluationventricular function is the combination of different methods: TAPSE, TDI and index ofmyocardial performance. Two-Dimensional (2D) Speckle-Tracking Echocardiography (STE)is a relatively new, angle independent technique that is used for the evaluation of global andsegmental myocardial function. Myocardial strain values regional ventricular deformation.Myocardial strain rate (SR) is a time derivative of strain and has shown to correlate linearlywith left ventricle (LV) peak elastance, which is a load-independent global measure ofventricular systolic function.

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Conclusion: New echo technology can identify early left and right ventriculardysfunction. This may allow earlier intervention and help to avoid irreversible damage to themyocardium in congenital heart disease.Chapter 4 Coronary artery anomalies are some of the most confusing, neglected topicsin cardiology. The occurrence of coronary artery abnormalities is reported to beapproximately 0.2% to 5,6 %. These anomalies are usually not symptomatic and have noclinical significance, although in some particular cases can be fatal. Recently CoronaryComputed Tomography Angiography, replaces the method of choice, coronary invasiveangiography, for detecting coronary anomalies, based on its ability to accurately depict theanatomy of the heart and thorax. A useful classification it is very important to understand thecomplex topic of coronary artery anomalies (CAAs). There are four types: Anomalies oforigination and course, anomalies of intrinsic coronary arterial anatomy, anomalies ofcoronary termination and anomalous collateral vessels. Each tipe has differents items that areshown in correlative figures in this chapter. The Malignant type, it is also reported asanomalous origination of a coronary artery from the opposite sinus (ACAOS) withintussusception of the ectopic proximal vessel, which is the subgroup of CAAs that has themost potential for clinical repercussions, specifically sudden death in the Young. It is veryimportant the adequate knowledge of these anomalies in order to achieve an appropriate andaccurate diagnosis, that can be the key for the good prognosis of this group of patients.Chapter 5 The ductus arteriosus plays a fundamental role in directing 8085% of theright ventricular output arising from the superior vena cava, coronary sinus, and a small partfrom the inferior vena cava to the descending aorta. Its histological structure is predominantlymade up by a thick muscular layer, different from the aorta and the pulmonary artery, whichincreases with gestational age. The fibers have a circumferential orientation, especially at theexternal layers, facilitating and making effective ductal constriction. These factors maygenerate lumen alterations, which may cause fetal and neonatal complications, such as heartfailure, hydrops, neonatal pulmonary hypertension, and even death. Classically, maternaladministration of indomethacin and/or other anti-inflammatory drugs interfere inprostaglandins metabolism, causing ductal constriction. However, many cases of fetal ductalconstriction, as well as of persistent neonatal pulmonary artery hypertension, remain withoutan established etiology, being referred as idiopathic. In recent years, a growing body ofevidence has shown that herbs, fruits, nuts, and a wide diversity of substances commonlyused in daily diets have definitive effects upon the metabolic pathway of inflammation, withconsequent inhibition of prostaglandins synthesis. This anti-inflammatory action, especiallyof polyphenols, when ingested during the third trimester of pregnancy, may influence thedynamics of fetal ductus arteriosus flow. The aim of this review is to present these newobservations and findings, which may influence dietary orientation during pregnancy.Chapter 6 Fetal cardiac arrhythmias (FCAs) detected during a routine clinical obstetricor ultrasonography examination constitute, in our experience, a relatively frequent findingand generate a marked anxiety in the family and the obstetrician. At least 2% of allpregnancies this problem is presented.In our 25-year experience (1988-2013) a total 203 FCAs was detected. 8 patients (p)(3,9%) with premature ventricular contractions; 53p (26,1%) with flutter or atrial fibrillation;66p (32,5%) with supraventricular tachycardia; and only 2p (0.98%) with ventriculartachycardia; 5p (4,5%) sustained sinusal bradycardia; 1p (0,5%) second-degree heart blockand 68p (33,5%) with complete atrioventricular block (CAVB).

Ral Cayr and Jos Milei

They manifest at any gestational age, as early as 13th week of gestation until the term.The association with cardiac malformations was more frequently in patients withcomplete congenital heart block 31 of 68 p (45.5%). The tachycardias they found wereassociated in 6 of 129p (4, 6%).The aim of the present chapter is to help to recognize the different FACs, carry out acorrect analysis, perform an adequate diagnosis and choose the best therapeutic behavior andfollow-up. The authors will therefore describe the different methods of analysis of the fetalcardiac rhythm (FCR), revise their disorder patterns, and describe their therapeutic optionsand responses.Conclusion: FCAs impose an emergency for the cardiologist since they generate amarked anxiety in both the family and the obstetrician. In flutter and fibrillation as well as inSVT the association of hydrops and/or cardiac malformation does not imply a bad prognosissign. Hospital admission should be limited to the presence of hydrops or prematurity before26th week of gestation according to our criteria.In CAVB, the presence of hydrops, FCF< 50 bpm and/or the association to cardiopathiesare of very bad prognosis. In the cases without malformation with maternal positiveantibodies, the treatment with corticoids must be performed promptly after maternal bloodextraction.Fetal-maternal Doppler of umbilical and middle cerebral arteries gives us the possibilityof ruling out hypoxic component, and it must only be taken into account thatcerebral/umbilical resistance index relation must be >1 whatever the gestational age.Doppler of ductus venosus, suprahepatic veins and umbilical veins must be controlledsince they may allow distinguishing fetuses with higher risk of developing hydrops.Chapter 7 This chapter is an actualized review of different aspects related to pulmonaryhypertension associated with congenital heart disease. The main message that they try toconvey to the readers is the importance of early diagnosis and treatment of congenital heartdisease, to avoid pulmonary vascular disease; this means, the importance of prevention ofpulmonary vascular disease. Considering that left to right shunts are the more frequentcongenital heart disease associated with pulmonary hypertension, this topic is analyzed inwide form, from physiopathology until treatment, emphasizing the importance of a clinicalapproach for early detection of Congenital Heart Disease. I propose a pyramidal approach tothe diagnosis and treatment of congenital heart disease associated with pulmonaryhypertension.The authors emphasize that it is not correct to extrapolate the result of studies made inadults and apply it to children. I mention that the Dana Point Classification (with the Updateof Nice) is difficult to apply to children; for this reason I see that it is more applicable to usein pediatric patients the, Panama Classification: Classification of pulmonary vascular diseasein children.I give special importance to two topics: The adult with congenital heart disease andPulmonary Hypertension, including the Eisenmenger Syndrome, and pulmonary hypertensionassociated with congenital heart disease at altitude. This last topic is very important,considering that a great population lives at high altitudes (more than 140,000,000 people); onthe other hand, hypobaric hypoxia gives a special characteristic to pulmonary hypertension athigh altitude, which influences biopathogenesis, clinical aspects, diagnostic approach andtreatment.

categories of complex cardiac malformations that, in the context of congenital heart diseases,exemplify one of the most challenging objectives of the study. The management of patientswith an anatomical or functional single ventricle represents an unlimited task in thepediatric cardiology and surgical field. The vision of this matter in this undone chapter canbe summarized in three stages: the prelude, the epic and the future. In the early 1940s, thepreface era, an experimental work inspired what is named nowadays as the Fontan/Kreutzeroperation the total right ventricular bypass was first reported in humans in the early 1970s.In the following 40 years several modifications and refinements of the initial surgical design,improved perioperative care and management of algorithms-based protocols produced adrastic increase in perioperative survivors the heroic epic. However, when patients grewinto adulthood, coping with a complete univentricular circulation as a result of the palliativeprocedures, they faced numerous complications and multi-organ system difficulties thatseriously limited their quality of life. Continuous research and multidisciplinary efforts inseveral directions are needed to answer the future of Fontan failure patients. Perhaps thiswould include the expected potential clinical application of a mechanical new neosubpulmonary ventricle compatible with a normal life span similar to people with a normalbiventricular circulation.Chapter 9 Restrictive cardiomyopathy is a rare disease in childhood characterized byventricular diastolic dysfunction usually with preserved systolic function, with a progressiveclinical course and poor outcome. This chapter reviews the definition, epidemiology,genetics, natural history, clinical presentation, role of diagnostic tools, outcome, and currentmanagement of pediatric populations with this uncommon disease based on our clinicalexperience and literature studies. Restrictive cardiomyopathy in childhood is a rare entitywith high mortality rates that still arises controversy around its definition and treatment. Thestratification of risk factors for sudden death, cardiac failure, thromboembolic events andincrease in pulmonary vascular resistance requires prospective longitudinal studies with largepediatric populations in order to acquire better knowledge of the course and outcome of thisdisease. The identification of specific genetic mutations is paving the way for a betterunderstanding of the molecular pathology of restrictive disorders. This line of research willmost probably lead to the design of new therapies that can delay or reduce the need for hearttransplant.Chapter 10 TRANSCATHETER CLOSURE OF ASDs- PFOs: The type, size, andshape of atrial septal defects (ASDs) can vary greatly. Ostium secundum (OS) are the mostcommon ASDs, are present in the region of the fossa ovalis, and account for 75% of allASDs. The position and size of the ASDs, number of defects, distance between the defects,type of defects, and relationship with other structures must be determined to result in asuccessful procedure. ASDs that are not suitable for trans-catheter device closure are sinusvenous defects (4-11%) and ostium primum ASDs (15-20%).TRANSCATHETER CLOSURE OF VENTRICULAR SEPTAL DEFECTS (VSD):Common congenital heart disease (20%). Indications for VSD closure are: symptoms of heartfailure; signs of volume overload in left heart chambers; history of endocarditis; and postoperatory residual VSD with volume overload. The procedure is not recommended in absenceof the crista since this type of VSD has a deficient aortic and pulmonary margin. The riskfactors for complications are age (<5 months) and weight (<5 kg), which are associated with ahigher risk of early complications. The localization of the defect: pm VSD has an increased

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risk of complete cAVB after device implantation. The success rate was very high, as closurewas successfully achieved in 95.3% of subjects in the follow-up.AORTIC COARCTATION: Occurs in about 0.04% of live births and comprises about7% of known congenital heart disease. Surgery is the best option in native coarctation inpatients <25 kg and covered stent in patients >45 years old, to avoid morbidity. Inpostsurgical residual gradient, the best option is angioplasty or stent, depending on age, typeof defect, elasticity of the wall and other complications. If the aorta must be expanded to adultsize, or when the initial measure requires a final diameter 3 times greater, covered stent ispreferred.Conclusion: Therapeutic intervention helps in congenital heart disease by solving anincreasing number of pathologies and is complementary to other surgical lesions.Chapter 11 Evolving surgical and catheter-based techniques and a collaborationenvironment between surgeons and interventionalists resulted in the advent of the so-calledhybrid procedures in congenital heart disease. Although the hybrid approach starts with acollaborative effort between surgeons and interventionalists, it continues with carefulplanning among different subspecialties such as imaging, intensive care and anesthesia. Thegoals of hybrid therapies include reduction of morbidity and mortality in patients with morecomplex diseases, mitigation of the negative cumulative effects of multiple procedures,improvement in quality of life and delivery of a more cost-efficient care. Also the hybridenvironment encourages the sharing of expertise, ideas, equipment and techniques, which iscrucial to introduce novel therapies for challenging patients. These procedures havesignificantly expanded the therapeutic options for several patients with complex congenitalheart disease in the last 10 years. In this chapter the authors will discuss the application of thehybrid approach in the management of hypoplastic left heart syndrome, muscular ventricularseptal defects and pulmonary artery stenosis.Chapter 12 The surgical management of transposition of the great arteries withventricular septal defect and left ventricle outflow tract obstruction is a true challenge incongenital heart surgery. Different surgical techniques such as the Rastelli procedure,Reparation a` lEtage ventriculaire, the Metras modification, Nikaidoh operation and itsmodifications were defined.Although the Rastelli operation has been the most widely performed surgical procedureover the past decades, several studies have shown suboptimal long-term prognosis after itspractice. A newer operation described by Bex and Nikaidoh has been performed withpromising outcomes. The anatomical characteristics usually enable biventricular repair,though in some hearts univentricular palliation may be the only surgical option.Chapter 13 Major advances and refinement in the diagnosis and surgical treatment ofcongenital heart defect in the last four decades has resulted in an increasing number of adultsurvivors.The incidence of congenital heart diseases is around 1%. Nearly 6000 children are bornwith one congenital heart defect in Argentina per year. Two thirds of them require surgicaltreatment mostly within the first year of life. Fortunately, surgical mortality has been reducedto low single figures in the last 20 years and 90% of the operated patients are expected toreach adulthood. It is noteworthy that congenital heart surgery is reparative and notcurative. Except for the ligated patent ductus arteriosus in the first months of life, allcongenital heart lesions whether operated on or not will require lifelong control. Even the

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Atrial Septal Defect (ASD) operated upon in the first years of life may be exposed to thedevelopment of atrial fibrillation or sick sinus disease in the fourth decade.Chapter 14 Children with congenital heart disease require adequate clinical support.Intensive care units (neonatal and cardiovascular) and pediatric emergency departments havea vital role in the care of these patients. This chapter presents the key aspects for propermanagement of these children: early diagnosis, timely treatment, clinical support andprevention and treatment of complications.

AbstractThe embryological development of the coronary arteries in humans is stillcontroversial. It is unclear whether there is a dual process of angiogenesis andvasculogenesis or a single process of vasculogenesis. Objective: This chapter examinesthe development of the coronary arteries in human embryos within the context of recentexperimental findings. Methods: Of 131 human embryos and fetuses, 22 between stagesXIII (272 days) and XVIII (481 day) were studied. Results: Islands of angioblasticcells appeared in stage XIII. By stage XV two distinct subepicardial vascular networkswere seen which connected to the aorta by stages XVII-XVIII. Endothelial indentationswere seen in stages XV and XVI only in the region of the aorta just above the developingaortic sigmoid valves; no direct connections could be confirmed to the subepicardialvascular network therefore we cannot conclude that these are involved in the formation ofthe proximal coronary trunks as has been previously proposed. Compaction of theventricular myocardium began in stage XV at the base of the heart and extended towards*

E-mail: raul.cayre@gmail.com.

Julio D. Civetta, Lilliam M. Valdes-Cruz and Raul O. Cayre

the apex. Conclusion: The coronary arteries in the human embryo seem to developthrough vasculogenesis with the appearance of islands of angioblastic cells whichcoalesced to form two subepicardial capillary networks; these were clearly distinct bystage XV. The connection of both vascular networks via coronary channels to the aortawas invariably present by stage XVIII.

IntroductionThe embryological development of the coronary arteries in humans continues to becontroversial. Descriptive studies in human embryos have considered it to be a dual processof angiogenesis, that is the sprouting of new vessels from the aorta, and of vasculogenesis, theorganization of a vascular plexus from the de novo differentiation of angioblastic cells locatedin the epicardial region which later remodel into definitive vessels. [1-5] This dualmorphologic mechanism has also been proposed in descriptive and experimental studies invarious animal species such as rabbit [6, 7], pig [8], rat [9] and chick. [10, 11]However, other descriptive studies in human and rat embryos [12, 13] and experimentalstudies performed on quail, chick and chicken-quail chimeras [14-25] questioned this dualorigin of the coronary arteries. Instead, these authors postulated a single process ofvasculogenesis through which pericardial vessels penetrate the wall of the aorta by ingrowthfrom the peritruncal ring thereby establishing a connection with its lumen.In a recent review of the latest studies on the origin and development of the coronaryarteries, Silva-Junior, et al. summarize the current understanding of the process as a series oftemporally regulated events including vasculogenesis, angiogenesis, arteriogenesis andremodeling. [26]In this chapter we reexamine data on the development of the coronary arteries in humanembryos within the context of these recent experimental findings.

Material and Methods

The authors had access to a collection of 131 human embryos and fetuses all products ofspontaneous abortions or ectopic pregnancies. Of these, 22 embryos were found to bebetween stage XIII (272 days) and stage XVIII (481 day) according to Streeter GL [27] yPineau H [28], having a crown-rump (CR) length between 4.5-18 mm. These constitute thematerial selected.The younger embryos were fixed in 10% formaldehyde and the older ones in Bouinsolution. They were embedded in paraffin and serially sectioned in axial cuts (20 embryos) orin sagittal cuts (2 embryos). The thickness of the serial histologic sections ranged from 7umto 20um. Those in stages XIII-XVI were stained with hematoxylin and eosin and those instages XVII-XVIII with either Mallory Heindenheim or hematoxylin and eosin. They wereanalyzed with biological photomicroscopes Olympus CX 40 and Nikon Eclipse E200 andphotographed with an Olympus SC 35 Type 12 camera and with a Nikon Coolpix 5000digital camera. Two wax reconstructions following the method of Born [29] were made from

Observations on the Development of the Coronary Arteries in the Human Embryo

one embryo measuring 18mm CR length: one of the entire heart and another of the lumina ofthe coronary arteries connected to the lumen of the aorta.

ResultsTable 1 summarizes the data on the 22 embryos examined. As previously reported byHutchins, et al [30], some morphologic findings were found abruptly in one stage, whileothers appeared more gradually over two or even three stages in individual human embryos.For this reason we report our observations as the sequence of events observed in the variousstages.Table 1. Summary of embryos analyzedN

Julio D. Civetta, Lilliam M. Valdes-Cruz and Raul O. Cayre

Stage XIIIIslands composed of angioblastic cells (erythroblasts or nucleated erythrocytes) wereobserved in the parietal pericardium in front of the conus and of the anterior wall of theprimordium of the trabeculated portion of the left ventricle (Figure 1 A, B). Angioblastic cellswere also found in the subepicardial space of the ventricular wall at the level of the anteriorinterventricular sulcus and in the diaphragmatic wall of the ventricular pouch (Figure 1C, D).These islands had no connection to each other or to the ventricular cavity. The ventricularmyocardium had a spongy appearance particularly in the trabeculated pouch of the leftventricle (Figure 1C, D).

Figure 1. Microphotographs of axial cuts of a stage XIII 4.5 mm crown-rump (CR) length humanembryo MAM-1 (Panels AD) and of a stage XIV 5mm CR length human embryo PAU-3 (Panels EG). A: Angioblastic cells (arrow) in the parietal pericardium in front of the conus. B: Angioblastic cells(arrows) in the parietal pericardium in front of the anterior wall of the primordium of the trabeculatedportion the left ventricle. C: Angioblastic cells (arrow) in the anterior interventricular sulcus. D:Angioblastic cells (arrow) in the diaphragmatic wall of trabeculated pouch of the left ventricle. E:Blood islands (arrows) in the ventricular wall adjacent to the anterior interventricular sulcus. F: Primarycapillary (arrows) in the ventricular wall at the level of the posterior interventricular sulcus. G: Spongymyocardium with numerous trabeculae and vascularization dependent on the ventricular cavity.(Hematoxylin-eosin stain). Co: conus; P: pericardium; TP: trabecular pouch.

Observations on the Development of the Coronary Arteries in the Human Embryo

Figure 2. Microphotographs of sagittal cuts of stage XV 8mm CR length human embryo TEMAR-2. A:Subepicardial vascular network (arrow) along the right atrioventricular sulcus. B: Subepicardialvascular network (arrows) on the diaphragmatic wall of the ventricles. C: Subepicardial vascularnetwork (arrows) on the anterior wall of the right ventricular outflow tract. D: Beginning of compactionof the ventricular myocardium along the base of the heart. E: Subepicardial vascular network (arrows)in the anterior wall of the right ventricle. (Hematoxylin-eosin stain). RA: right atrium; RAVS: rightatrioventricular sulcus; RV: right ventricle.

Stage XIVA larger number of blood islands were observed in the walls of both ventricles near theinterventricular sulcus (Figure 1E, F). Some islands coalesced having the appearance ofprimary capillaries with nucleated erythrocytes forming a rudimentary subepicardial vascularnetwork (Figure 1F). The ventricular myocardium had a more spongy appearance withnumerous trabeculae and vascularization dependent on the ventricular cavity (Figure 1F, G).

Stage XVMore advanced development of the subepicardial vascular network was appreciated withtwo clearly distinct networks (Figures. 2, 3). The more developed one was located along theright atrioventricular sulcus (Figure 2A), the posterior interventricular sulcus, thediaphragmatic wall of both ventricles (Figure 2B) and the anterior wall and outflow tract of

Julio D. Civetta, Lilliam M. Valdes-Cruz and Raul O. Cayre

the right ventricle (Figure 2C, E). The less developed network was found in the anteriorinterventricular sulcus (Figure 3A), the adjacent areas of both ventricles (Figure 3B, C) andthe left atrioventricular sulcus (Figure 3D). At this stage the vascular networks had notreached the peritruncal region.In one embryo (TEMAR 2, stage XV), a blood island of nucleated erythrocytes was seenin the region of the sinus venosus adjacent to the right atrioventricular sulcus (Figure 3E).In this stage we noted the start of the process of compaction of the ventricularmyocardium at the base of the heart. The ventricular apex had a spongy, non compactedmyocardium with trabeculae (Figure 2D). In some areas the lumen of the ventricular cavityalmost reached the pericardium.In this same stage we observed small indentations of the aortic endothelium in severalareas of the aortic root, in the region of the developing aortic sigmoid valves. Theseindentations did not extend beyond the endothelial layer (Figure 3F).

Stage XVIThere was a more developed subepicardial vascular network (Figure 4A-C). Theindentations of the aortic wall already seen in stage XV were again observed in this stage;these were not connected to the subepicardial vascular networks (Figure 4D). We also notedthe presence of intercalated truncal swellings, the beginning of the formation of the aorticsigmoid valves.

Stage XVIIThere was marked development of the subepicardial vascular networks (Figure 5) withappearance in the peritruncal region (Figure 5A, B).The process of myocardial compaction was further developed and now was seen in theregion of the cardiac apex (Figure 6A). In one embryo, TE-10, there were intramyocardialsinusoids which connected the subepicardial network with the ventricular cavity(Figure 6B, C).In embryo JU-4, there was a left coronary channel connecting the subepicardial networkto the aortic lumen, corresponding to the origin of the left coronary artery (Figure 7A-C).There was also a right coronary channel connecting the subepicardial network to the aorticlumen, corresponding to the origin of the right coronary artery (Figure 7D-F); this occupied amore cephalic position with respect to the left coronary channel.

Observations on the Development of the Coronary Arteries in the Human Embryo

Stage XVIIIAll embryos of this stage demonstrated the origins of the left and right coronary arteriesand their respective connections to the corresponding subepicardial vascular network (Figure8). The wax reconstruction of embryo GON-2 (Figure 8F) shows the origin of the right andleft coronary arteries emerging from the aorta and the spatial position of the proximalsegments with the right being in a more cephalic plane than the left.

DiscussionOur observations in 22 human embryos stages XIII-XVIII demonstrate that the firstfeature in the development of the coronary arteries is the appearance, through a process ofvasculogenesis, of islands of angioblastic cells (erythroblasts) in the parietal pericardium infront of the conus, and of the anterior wall of the primordium of the trabeculated portion ofthe left ventricle, in the subepicardial space of the ventricular wall adjacent to the

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interventricular sulcus and near the cardiac apex (Figure 1A-D). To our knowledge, this is thefirst time these findings are described in a stage XIII human embryo. We documented theprogression of the vasculogenetic process during stage XIV (Figure 1E, F) with the formationof subepicardial capillaries resulting from coalescence of the blood islands and the beginningsof a subepicardial capillary network. This has been previously reported in human embryosduring stages XIV [3, 4, 30, 31], XV-XVI [12] and XVI-XIX [32]. A similar vasculogeneticprocess has been observed in chick embryos [10, 18-20] and in chicken-quail chimeras. [22]By stage XV (Figures 2, 3), two clearly distinct subepicardial vascular networks wereseen which have been previously reported as the origins of the right and left coronary arteries.[4] Distinct coronary channels were seen only in the regions corresponding to the right andleft coronary arteries (Figure 7). The connection of the subepicardial vascular network to theaortic lumen was seen in one stage XVII embryo but was invariably present in all stage XVIIIspecimens (Figure 8). None of our stage XVII or XVIII embryos had an earlier origin of theleft anterior coronary artery as has been reported by other authors. [3, 12, 13]During stages XV and XVI we observed indentations of the aortic endothelium in severalareas around the aortic root, in the region of the developing aortic sigmoid valves (Figures.3F, 4D).

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Figure 8. Microphotographs of axial cuts of stage XVIII 18mm CR length human embryo GON-2.Photograph of three-dimensional wax reconstruction of the same embryo. A: Ostium of the rightcoronary artery and distal section of same (arrows). B: Tangential section of the right coronary artery(arrow). C: Transverse section of the right coronary artery and one of its branches (arrows). D: Ostiumof the left coronary artery and longitudinal section of same (arrows). E: Longitudinal section of the leftcoronary artery (arrow). F: Three-dimensional wax reconstruction of the area corresponding to theaortic sigmoid valves and proximal portions of the right and left coronary arteries (arrows). (TrichromicMallory Heindenheim stain). Ao: aorta; Aol: aortic lumen; LCA: left coronary artery; RCA: rightcoronary artery.

These indentations were restricted to the endothelial layer of the aorta and we could neverdemonstrate direct connections to the subepicardial vascular network. Several authors havedescribed indentations in the aortic endothelium just above the developing sigmoid valves inhuman embryos [1, 3-5, 32, 33], in embryos of rabbit [6, 7], rat [9], chick [10, 11] and pig [8]and have called them aortic endothelial sprouts or coronary buds. It has been speculated thatthese endothelial indentations represented the primitive coronary arterial system which laterconnected with the vascular network thereby concluding a dual process of angiogenesis andvasculogenesis. However, upon careful analysis of these publications we failed to finddefinitive evidence that the indentations shown either reached the media of the aortic wall orconnected directly to the vascular network. In their study of human embryos, Hutchins, et al[30] mentioned the presence of small indentations of the endothelium into the arterial walls.They interpreted these as secondary changes possibly due to contraction of the vessels duringhistological preparation and specifically stated no clear evidence of endothelial sprouts orincipient coronary artery in any embryo. Nonetheless, they speculated that the coronaryarteries do arise presumably from these attempts at endothelial outgrowths which are

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successful only at the points where the wall tension of the aorta is elevated. Conte andPellegrini [4] also mention the presence of multiple coronary buds in the aortic wall as well asin the wall of the pulmonary artery. No embryo in our series had endothelial indentations inthe pulmonary arterial wall. Since we did not find direct connections of the endothelialindentations to the subepicardial vascular network, we cannot conclude that they are involvedin the formation of the proximal coronary trunks.Our observation in a stage XVII embryo of coronary channels connecting thesubepicardial networks with the aortic lumen, (Figure 7) would be consistent with a processof vasculogenesis starting from the subepicardial vascular network. Recent experimentalembryology studies in different animal species have also denied the existence of coronarybuds and negated a process of primary angiogenesis from the aorta. [12-15, 18] These authorsconcluded that, as a result of a process of vasculogenesis, the subepicardial vascular networkspenetrate the wall of the aorta through coronary channels thereby establishing theirconnection to the aortic lumen, and not vice versa. Experimental studies conducted in chick,quail and chicken-quail chimeras have shown that the endothelial and smooth muscle cells ofthe coronary arteries have a different cell lineage from the endothelial and smooth musclecells of the aortic walls. [16, 19-23, 25] These results would lend convincing evidence infavor of a single process of vasculogenesis. [34-36]Recent experiments using retroviral tracers in chicken-quail chimeras have shown thatthe endothelial and smooth muscle cells of the coronary arteries originate from theepicardium. [19, 23] Experimental studies using monoclonal antibodies in quail embryos[16], retroviral cell tagging techniques in chick embryos [19, 21] and antiendothelialantibodies in chicken-quail chimeras [22] have suggested that the cells that will give rise tothe epicardium originate from epithelium associated with the septum transversum. Later itbecomes a structure composed by transient extracardiac mesothelial cell population whichcomes to lie between the liver and the sinus venosus and has been called the proepicardialorgan (PEO). From there, cells migrate to the sinus venosus and later to the atrioventricularsulcus and the ventricular wall adjacent to the interventricular sulcus. To the best of ourknowledge, the existence of a PEO has not been demonstrated in the human embryo. In fact,the early location of the precursors of the epicardium, myocardium and endocardium in thehuman embryo is still under debate. [37, 38] In this context, it is interesting to note that weobserved in one embryo (TEMAR-2, stage XV) angioblastic cells in the region of the sinusvenosus, adjacent to the right atrioventricular sulcus (Figure 3E) as well as angioblastic cellsalong the atrioventricular sulcus, the diaphragmatic wall of both ventricles and at either sideof the interventricular sulcus (Figure 3B, D).Recently, Ando, et al. [39], using double immunostaining and confocal microscopy inquail embryos concluded that the initial formation of the proximal coronary arteries consistsof endothelial strands which penetrate the aortic wall at several sites. Only those at the facingsinuses fuse to form the proximal right and left coronary arteries and develop a medial layerthereby demarcating the definitive coronary arteries from the aortic media. They suggestedthat these strands are derived from mesenchymal cells, probably endothelial progenitorsoriginating from the so-called proepicardial organ (PEO), as was already mentioned by otherauthors. [16, 21, 25]More recently, Red-Horse et al. [40], using histological and clonal analysis in mice andcardiac organ culture, propose that coronary vessels have two sources of progenitors. Themajor source are differentiated venous endothelial cell originated from angiogenic sprouts of

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the sinus venosus, which proliferate and spread to form the coronary plexus, and subsequentlyredifferentiate and remodel into coronary arteries, capillaries and veins. The minor secondarysource is the endocardium, from which cells separate to form blood islands and then join thecoronary plexus near the interventricular septum.Wu and colleagues [41] propose a major ventricular endocardial origin for coronaryarteries. Using a NFATc1-Cre mouse line the authors trace ventricular endocardial cells to theforming vascular outline of the arterial portion of the coronary system with a few markedcells found in coronary veins. However, the authors do not exclude contributions from othersources, or distinct origins in other species such as chick.Pires-Gomez and Perez-Pomares [42], point to a diverse origin of the coronaryendothelium, where the arterial and venous systems have distinct origins at differentmorphological sites and in different stages of embryonic development. This will requirefurther effort to clarify the origins and the pathways involved in the assembly of this tissue.We noted that the process of compaction of the ventricular myocardium begins duringstage XV at the base of the heart and extends towards the apex (Figure 2D). This is inagreement with the findings of Agmon, et al. [43] Rychter, et al. state that the appearance ofthe coronary arteries coincides with the start of the compaction of the myocardium. [44]However, in our study angioblastic cells, the primordia of the coronary arteries, were detectedduring stages XIII and XIV, before any ventricular compaction was appreciated.In our series, the connection between the subepicardial vascular network and the leftventricular cavity through sinusoids was seen in one embryo stage XVII (Figure 6B, C). Thisconnection has been described in human embryos of stage XV [4, 32, 45] as well as in chickembryos [10, 18] and chicken-quail chimeras. [22] Hutchins, et al. [30] found only indirectevidence of communication between epicardial vessels and the ventricular cavity. Wepostulate that the reason coronary-cameral communications are not always seen is due to therapid regression of the intertrabecular spaces as the process of myocardial compactionprogresses.

ConclusionIn the context of recent experimental findings, our observations offers the followinginsights into human coronary morphogenesis: 1) the coronary arteries in humans seem todevelop through an embryonic process of vasculogenesis with the appearance of islands ofangioblastic cells seen as early as stage XIII. The organization of a vascular plexusprogressed with the coalescence of the blood islands to form a subepicardial capillarynetwork. By stage XV there were two clearly distinct subepicardial vascular networks. Theconnection of both vascular networks via coronary channels to the aorta may be seen in stageXVII but was invariably present by stage XVIII. 2) Endothelial indentations, documented instages XV and XVI, were seen only in the region of the aorta just above the site of thedeveloping aortic sigmoid valves. No direct connections were confirmed to the subepicardialvascular network, therefore we cannot conclude that they are involved in the formation of theproximal coronary trunks as has been previously proposed. 3) Angioblastic cells were seen inthe region of the sinus venosus in one embryo suggesting the possibility that these mayoriginate from the proepicardial organ. 4) The process of compaction of the ventricular

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myocardium began during stage XV at the base of the heart and extended towards the apex.5) Connection between the subepicardial vascular network and the left ventricular cavitythrough sinusoids was seen in one embryo stage XVII.

ININCA-UBA-CONICET, Buenos Aires, Argentina2Division of Cardiology, University of Perugia School of Medicine, Perugia, Italy1

AbstractCongenital heart defects (CHD) and/ or their repair process lead to an increased riskfor adult cardiovascular disease compared with the general population.Intimal hyperplasia is a pre-atherosclerotic lesion that may be produced as aconsequence of the activation of transforming growth factor beta-1 (TGF-1) pathway orER inhibition.This chapter deals with our recent findings in this regard and comments our latestresults in connection with relevant reports from other authors.We examined the coronary arteries from a pediatric population with CHD andevaluated the possible relationship between the frequency of intimal hyperplasia and themagnitude of TGF-1 in order to enlighten the possible role of TGF-1 in the genesis ofthese lesions. The coronary arteries of 10 control patients and 98 CHD patients (54%cyanotic type, 32% surgically repaired) were stained and assessed for the presence anddegree of intimal thickening. The expression of TGF-1 and ER was determined byimmunohistochemical examination.

Roco Castilla, Matilde Otero-Losada, Anglica Mller et al.

The frequency of coronary intimal hyperplasia did not depend on the group, i.e.:cyanotic CHD group (66%) and non-cyanotic CHD group (64%). However, thefrequency of coronary intimal hyperplasia was higher in patients with surgically repairedCHD than in patients without surgical intervention (80% vs. 47% respectively,p=0.0002).The degree of positive immunostaining for TGF-1 or ER did not depend on thegroup. i.e.: cyanotic and non-cyanotic type. On the other hand, examination of the intimallayer showed that TGF-1 expression was higher and expression of ER was smaller inpatients with surgically repaired CHD compared with those without surgery.The relationship between the frequency of intimal hyperplasia and the expression ofTGF-1 and ER in arteries from 98 pediatric patients with congenital heart defectsindicated that: 1) intimal hyperplasia was a common finding in the coronary tree of thesepatients, 2) both TGF-1 and ER seemed to play a major role in this phenomenon and 3)surgical correction of CHD was associated with further coronary vascular remodeling.

IntroductionCongenital heart disease (CHD) patients represent a risk group for prematureatherosclerotic coronary artery disease [1]. Certain congenital heart defects, or the process oftheir repair, may lead to an increased risk for adult cardiovascular disease compared with thegeneral population on the basis of two major mechanisms: abnormal coronary origin andobstructive lesions of the left ventricle and aorta [1,2]. Congenital anomalies of coronaryorigin have been reported to portend a high incidence of coronary atheromas, likely due toabnormal blood flow patterns [1]. On the other hand, patients with cyanotic CHD have beenreported to present a low incidence of coronary atherosclerosis due to hypocholesterolemia,up regulation of nitric oxide, hyperbilirubinemia and low platelet count [3].Years ago fatty streaks were described as the earliest manifestation of atherosclerosis [4].However, the proliferation of intimal smooth muscle cells (SMCs), which causes intimalthickening prior to any visible lipid deposition, was proposed to be the initial lesion [5-8].Coronary intimal hyperplasia/thickening consists primarily of proliferation of SMCs,which are -actin positive, surrounded by a proteoglycan-rich matrix but rarely havemacrophages [9-11].The increasing trend to consider coronary intimal thickening as a possiblepreatherosclerotic lesion [9-11] is based on several findings. First, some papers show thatatherosclerotic lesions arise almost exclusively from intimal thickenings in the coronaryarteries of hypercholesterolemic swines [12]. Also, a correlation was established between thedistribution of intimal hyperplasia in children and the localization of characteristicatherosclerotic lesions observed in adult humans (i.e. first segment of the left anteriordescending coronary artery) [13,14]. Additionally the majority of erosions occur over areas ofintimal thickening, with minimal or no presence of a lipid core [9]. We previously found thatearly coronary artery lesions may range from focal areas with mild myointimal thickening inprenatal life to early soft plaques in infants, with c-fos gene activation in the SMCs of themedia of coronary arteries, which may also present as intermingled lesions with componentsof both categories, more frequently observed with increasing age [11-15].Of note, in 1976 Becu et al. described varying degrees of coronary lumen occlusionsconsisting of prominent intimal proliferation of (SMCs), media muscle disarray and

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fragmentation and/or disappearance of the internal elastic lamina in patients aged 6 days to 9years subjected to pulmonary valvotomy for isolated pulmonary valve stenosis [16].The transforming growth factor beta 1 (TGF-1) and the estrogen receptor alpha (ER)might be involved in the intimal hyperplasia formation [17].TGF-1 is a secreted multifunctional factor that modulates proliferation of many celltypes, including vascular cells, and regulates their interaction with the extracellular matrix. Itssignaling plays pivotal roles in SMC differentiation during vascular development and isinvolved in the development of many cardiovascular diseases [18,19].Smooth muscle cells are capable of reversibly modulating their phenotype duringpostnatal development and can de-differentiate into proliferative matrix synthetic cells inresponse to vascular injury [17-20]. Transforming growth factor-1 regulates both SMCdifferentiation during embryonic development and postnatal phenotypic switching [21]. Inthis connection, it was observed that over-expression of TGF-1 in normal arteries resulted insubstantial extracellular matrix production accompanied by intimal and medial hyperplasia[22].On the other hand, estrogens play an important role in cardiovascular protection.Estrogens stimulate endothelial cell proliferation in the vasculature [23], while inhibitingvascular smooth muscle cell (VSMC) proliferation [24] and migration [25], i.e.: two key stepsinvolved in intimal hyperplasia [10,15]. Estrogens induce a variety of effects throughinteraction with three estrogen receptors (ER): receptor- (ER), receptor- (ER), andtransmembrane G protein coupled estrogen receptor (gpER) [26]. Estrogen receptor alphaappears to be largely responsible for the protective effects of estrogens against atheroscleroticvascular disease [27-29] and mediates the inhibition of the vascular injury response byestrogen [30]. It is noteworthy that ER expression has been previously observed in the arterialwall of both men and women [31,32] suggesting a possible role for ER in vascular functionaside from its typical function in fertility.The possibility of reviewing the original microscopic slides belonging to Becus pioneerpaper [16] encouraged us to evaluate the frequency of coronary intimal hyperplasia in CHD inorder to assess a connection with the observed accelerated atherosclerosis in patientspresenting: 1) abnormal coronary origin 2) surgical repair 3) obstruction of the left ventricleand aorta, 4) cyanotic and non-cyanotic heart disease, and to get insight into the possible roleof TGF-1 and ER in the genesis of these lesions as well.Presence of intimal thickening in arteries was studied in 350 coronary artery samplesbelonging to 98 patients (range 15 days-9 years, mean age 2.4 years) of the CHD group and10 controls.Intimal proliferation was defined as muscle-elastic thickening characterized by: a)proliferation of SMCs; b) scarce monocytes, and rare lymphocytes, embedded by amorphousdeposits within the internal elastic membrane; c) endothelium above the lesionmorphologically intact, with smooth surface and devoid of thrombi [11,15]. Differentialdiagnosis with intimal ridges responsible of vessel bifurcation was made with the aid of serialaxial sections and longitudinal sections.Sixty percent (61%) of the CHD cases and all control patients presented at least onecoronary vessel with intimal hyperplasia. Hyperplasia was highest in the left main coronaryartery (LMCA) followed by the right coronary artery (RCA), the left anterior descendingcoronary artery (LAD) and posterior descending coronary artery (PDCA), and the circumflexartery (CX).

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Most patients presented complex cases with combined CHD. As an example, a 15 daysold patient, 2.62 kg weight, 29 cm height, with a heart of 25 g, showing pericarditis,perimembranous ventricular septal defect, right aortic arch and polycystic kidney. In thehistological study, the LMCA presented coronary intimal hyperplasia with two components:the first in contact with the arterial lumen resembling a soft plaque with scarce nucleisurrounded by loose connective tissue, and a second component in contact with the medialayer characterized by smooth muscle cell proliferation and dense connective tissue(Figure 1).Therefore, the combination of multiple structural anomalies in one same patient made itdifficult to link the occurrence of intimal hyperplasia to one specific congenital heart disease.In 81 out of 98 autopsies a correct assessment of the coronary origin was made, in theremaining 17 cases there was discrepancy among observers given the reduced size of thehearts. Nine out of 81 patients were found to have anomalous coronary origin. Among thesepatients with anomalous coronary artery origin eight presented at least one vessel with intimalhyperplasia.

Figure 1. Soft plaque in a CHD patient. Left coronary trunk from a 15 days old female patientpresenting an interventricular communication type I, pericarditis and polycystic kidney. A plaque withtwo components can be seen; the first is in contact with the lumen and resembles a soft, hypocelularplaque, with few nuclei belonging to mononuclear cells surrounding the loose connective tissue (grayarrow). The second, in contact with the media layer, is characterized by SMC proliferation and denseconnective tissue (black arrow). It should also be noted the interruption and duplication of the limitingmembrane, due to a severe media layer distortion and SMC proliferation. (H-E stain, X40). Reprintedfrom Ref. [42].

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Intimal Hyperplasia in Patients

with Cyanotic and Non-Cyanotic CHDFifty-four percent of the CHD cases were of the cyanotic type. Difference betweenpresence of coronary intimal hyperplasia in patients with cyanotic CHD (66.1%) and noncyanotic CHD (64.3%) did not achieve statistical significance (Fishers exact test, p=0.735).

Figure 2. Diffuse intimal thickening in an artery of a CHD patient. Surgically corrected tetralogy ofFallot in a male patient that shows diffuse intimal hyperplasia in the right coronary artery (A), leftanterior descending coronary artery (B), left main coronary artery (C), with a normal circumflex artery(D). (A and C: H-E stain, B: Victoria Blue stain, A to C: X25 and A to C: X10. Reprinted from Ref.[42].

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These findings would imply that cyanosis should have no role in influencing CHDpropensity to develop atherosclerosis. Yet, the available information suggests that theincidence of atherosclerosis is low in cyanotic CHD [3]. However, it must be noticed thatcoronary angiography, as used by Fyfe et al. [3], is not well suited for visualizing non-raisedlesions which do not significantly reduce visible vessel lumen, and therefore the actualfrequency of coronary disease may be underestimated. Furthermore, these patients presenthypocholesterolemia, up-regulation of nitric oxide, hyperbilirubinemia and low platelet count,all factors that may contribute to reduce the formation of atherosclerotic plaque.

Intimal Hyperplasia in CHD Patients

with Surgical InterventionThirty-two percent of the cases of CHD with surgical repair were also analyzed. Eightypercent of these patients died within one month of surgery because of complex CHD,hemodynamic impairment and difficult surgeries (Figure 2).Surgically repaired CHD presented a higher number of coronary intimal hyperplasia thanthe group without surgical intervention. Given that some patients may present only oneaffected vessel while others may have several, two criteria were used for comparison: 1)Percentage of coronary arteries with intimal hyperplasia and 2) Percentage of patients with atleast one coronary artery with intimal hyperplasia.Eighty percent of surgically repaired CHD patients presented at least one coronary arterywith intimal hyperplasia in contrast with 47% observed in the non-surgical group (two-tailedFishers exact test, p=0.0002). In addition, 68% of coronary arteries of the surgically repairedgroup presented intimal hyperplasia in more than one artery compared with 25% in the CHDgroup without intervention (Fishers test, p<0.0001). Age and sex were discarded as possibleconfounding variables.In view that most patients died within a month of the surgical intervention because of theseverity of the CHD it is difficult to determine whether the observed lesions were permanentor transient.

Intimal Hyperplasia in CHD Patients with

Obstruction of Left Ventricle or AortaThe group included aortic coarctation (31%), subaortic stenosis (8%) and aortic valvularstenosis (61%) with left ventricular hypertrophy. All the patients presented coronary intimalhyperplasia compromising at least one vessel. The rest of the congenital cardiopathiespresented this condition in 61% of the cases. The difference between both groups wassignificant (two-tailed Fishers test, p=0.0039). Special mention deserves the case of a 10years old male patient presenting subaortic stenosis, left ventricular hypertrophy andmoderate mitral insufficiency. The coronary tree showed intimal hyperplasia in each mainvessel, with the exception of the CX. The LMCA presented a diffuse and incomplete intimalthickening that occluded 55.4% of the arterial lumen (Figure 3).

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The fact that all patients with congenital subaortic stenosis, coarctation of the aorta andleft ventricular hypertrophy, presented coronary intimal hyperplasia may lend support toepidemiologic studies revealing that this group has a higher risk for developing coronaryatherosclerosis [1]. Coarctation of the aorta is linked to systemic hypertension [33] and leftventricular hypertrophy is an independent risk factor for cardiovascular disease morbility andmortality in adults [2,34]. The association between intimal hyperplasia in these patients, andthe high risk of accelerated atherosclerosis described in epidemiological studies [1] areconsistent with the hypothesis that intimal hyperplasia can be observed as the firstatherogenic event [10,11,35].

Roco Castilla, Matilde Otero-Losada, Anglica Mller et al.

Figure 4. Immunohistochemical staining for TGF-1. Different patterns are shown. On the top row weshow immunostaining for TGF-1, its negative control stained with H-E to corroborate the absence ofnonspecific stain and Victoria Blue stain for elastic fibers (x40) performed on the proximal segment ofthe right coronary artery of a patient with transposition of the great vessels. In the middle row, differentpatterns of TGF-1 can be observed. A: Left coronary trunk from a 4 days old male patient, 48 cm high,3185 g weight. The autopsy revealed a 30 g heart with a truncus arteriosus and interatrialcommunication. X10. B: Right coronary artery from a 2 month female patient, 50 cm high, 2200 gweight, who presented coarctation of the aorta and biventricular hypertrophy. X25. C: Left coronarytrunk from a patient with truncus arteriosus. In bottom, proximal segment from the right coronary arteryis shown. In the bottom row the absence of TGF-1 expression can be observed in the population withno CHD, D- Right coronary artery from a 5 year old male patient who died from intracranialhypertension. E- Right coronary artery from a 9 year old male patient who died from meningitis. FRight coronary artery from a 7 year old male patient who died from acute hydrocephalus. Reprintedfrom Ref. [42].

Roco Castilla, Matilde Otero-Losada, Anglica Mller et al.

Immunohistochemistry for TGF-1

The expression of TGF-1 was analyzed in samples of CHD patients (Figure 4). Therewere no differences between cyanotic and non-cyanotic CHD patients (% of reactive area was37.2 12.2 and 25.9 4.9 respectively). Moreover, TGF-1 expression was almostundetected in any of the 10 cases of pediatric population (aged 9) presenting arterialcoronary intimal hyperplasia/ thickening but who died from causes other than CHD(Figure 4).On the contrary, when immunostaining for TGF-1 was analyzed in patients with orwithout surgical repair, a striking difference was observed between them (mean intimal areapositive for TGF-1: 50.43% vs. 15.91% respectively; two-tailed Mann-Whitney U-test,p=0.0005) (Figure 5).The non-parametric comparison of repaired CHD, non-repaired CHD and pediatricpopulation without CHD revealed that the difference was significant (Kruskal-Wallis test,p<0.0001) (Figure 6).

Figure 6. Quantification of immunostaining for TGF-1 in surgical and non surgical-repaired patients.Difference in the percentage of intimal area positive for TGF-1 between the surgical CHD group, thenon-surgical CHD group and the pediatric population with no CHD. Bars indicate maximum andminimum values. Reprinted from Ref. [42].

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The presence of intimal hyperplasia and TGF-1 expression was more evident in LMCAand RCA compared with the remaining coronary arteries though the differences were notsignificant.The relative degree of intimal hyperplasia (intima/media ratio) and the percentage ofintimal area stained with TGF-1 were not correlated (Spearman's rank correlationcoefficient= -0.2955, IC95% (-0.61 to 0.11, p=0.134).As stated above, TGF-1 has been identified as an underlying factor in reparative processafter injury in various organs [36] and the over-production of this growth factor has beenimplicated as one causative agent in tissue repair processes characterized by increasedproduction of extracellular matrix and fibrosis [37].The reasons why patients with CHD subjected to surgical repair present TGF-1 levelssignificantly higher are not completely clear. It may be speculated that cardiac surgery is acause of vascular injury that leads to activation of this pathway. Thus, a stressor during thesurgical procedure induces the production of TGF-1, which in turn leads to intimalhyperplasia. A stressor could be endothelial hypoxia-ischemia. This occurs during arterialclamping [38], external compression of the vessels, extracorporeal circulation or duringcardiac preservation before transplant. Hypoxia leads to an increase of TGF-1 in humanpulmonary artery [39] and human dermal fibroblast [40]. It has also been postulated thathypoxia could stimulate TGF-1 through changes in redox state [36]. On the other hand, thepatients that were submitted to surgery were the most hemodynamically impaired. Because ofthis, hypoperfusion and thus low shear stress would likely contribute to inflammation morethan in the non surgical patients. This would also contribute to the increase in intimalhyperplasia.It is not surprising that intimal hyperplasia was found in our control population. We havereported that pediatric patients develop intimal hyperplasia in the absence of substantial TGF1 expression [7,14]. However, the control group was constituted by children who died ofnon-cardiac disease. Our data seem to indicate that the mechanisms behind intimalhyperplasia are multiple: TGF-1 is remarkably increased in children with CHD, and evenmore so in those who are hemodynamically unstable and/or were subjected to surgery, andhence it may contribute to development of intimal hyperplasia in those subjects; on the otherhand, other factors, different than TGF-1 may operate in children who died from causesdifferent from CHD.Intimal hyperplasia may regress by apoptosis, may stay asymptomatic or it may retainlipids and evolve into atherosclerotic lesions [11]. However, the pathophysiology of surgicalpatients seems to be different due to TGF-1 activation. A study on coronary arteries of ratsthat over-expressed TGF-1 proved that this growth factor stimulates intimal hyperplasia richin extracellular matrix with reversibility of coronary intimal hyperplasia by apoptosis after 8weeks [41].Therefore, it seems that clinical implications of intimal hyperplasia in surgical patientsdue mainly to TGF-1 over-expression depend on the reversibility of these lesions once theadverse stimulus disappears. This is not the case of intimal hyperplasia found in the pediatricpopulation, as they do not appear to be related to activation of the TGF-1 cascade [11,42].On the other hand, we found no association between the degree of intimal hyperplasiaand TGF-1 expression. However, a high incidence of mild intimal hyperplasia was observedon surgical patients with intense TGF-1 expression, while severe intimal hyperplasia lesionsin non-surgical patients and in patients with no CHD were negative for TGF-1.

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A direct relationship between intimal hyperplasia and TGF-1 is difficult to investigate in

these patients because the signal transduction of TGF-1 is very complex and it interacts withmultiple agents. For instance vascular SMC growth can be stimulated or inhibited by TGF-1in vitro, depending on cell density, cell age, co-culture factors, and the concentration of TGF1 [43-45]. The identification of a second marker together with the TGF-1 may represent astep forward in the elucidation of these discrepancies.Likewise, it would be necessary an acute temporal study indicating the injury time, TGF1 expression and intimal hyperplasia development, difficult to obtain in human beings.The intimal hyperplasia has also an important role in restenosis after coronary stentplacement, in pulmonary hypertension and in coronary artery lesions after cardiac transplant[46,47]. Yutani et al. reported positivity for TGF-1 in the intimal layer of 80% of restenosedcoronary arteries [48]. Furthermore, TGF-1 administration previous to carotid balloonangioplasty resulted in more extensive intimal hyperplasia after the procedure [49].The hypoxic theory also might explain the increase of TGF-1 and posterior coronaryintimal hyperplasia after stent implant or balloon angioplasty as both interventions areassociated with arterial wall hypoxia and neo-vessels formation in the adventitial layer [50].

Immunohistochemistry for EROverall, ER expression was evident in all layers of SMCs of arteries (media,endothelium, and intima) and it was quantified as a percentage of the ER-positive area,considering the whole artery, media or intimal layers. No significant differences betweenmale and female patients were found in the areas studied (Figure 7).

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ER, ER and gpER expression was observed previously in the arterial wall of both menand women [31,32]. Consistent with our results, other authors have reported no sexdifferences in ER expression as well [51].Additionally, ER expression was comparable in cyanotic and noncyanotic CHD patients(Figure 8). Then, the ER expression obtained in the arteries of controls and CHD patientswas evaluated. No significant differences were observed between controls and non-surgicallytreated patients.Since surgery was previously found to impact the incidence of intimal hyperplasia,differences in ER expression within CHD patients were evaluated according to whetherpatients had undergone surgical repair or not. A higher staining of ER was evident in intimalthickenings from non-surgically repaired CHD patients compared with a lower expressionobserved in surgically treated ones (Figure 9A and B). When ER expression was quantifiedconsidering the whole artery, a significant decrease (p<0.05) was evident in surgicallyrepaired CHD patients (Figure 9C), which was almost entirely due to a striking decrease(61.6%) in the intimal layer of the coronary artery of surgically repaired CHD patients,whereas expression in the media was unchanged. This also indicated that the decreaseobserved was not a consequence of nonspecific degradation of the sample.

Roco Castilla, Matilde Otero-Losada, Anglica Mller et al.

Figure 9. Expression of ER in CHD patients with and without reparatory surgery. Arteries from CHDpediatric patients were used for immunological determination of ER. Representative arteries ofpatients with (Panel B) or without reparatory surgery (Panel A) are shown. Immunohistochemistry wasperformed in the absence (Pictures 1 and 5) or presence of anti-ER antibody and observed at 3.5X(Pictures 1, 2, 5 and 6), 10X (Pictures 3 and 7) or 25X (Pictures 4 and 8). Bars indicate 20 m.

The relationship between CHD and intimal thickenings may involve differentmechanisms, whether direct or indirect, acquired or iatrogenic, and depending, in part, on thetype of defect and surgical intervention. For this reason, it is difficult to find an immediateexplanation for the reduction in ER expression. As stated above, as possible mechanisms, itshould be emphasized that hypoxia induces hypoxia-inducible factor (HIF-1), which is ableto repress the transcription of the ER gene in human breast cancer cells [52]. Both TGF-1and HIF-1 lead to increased proteasome-dependent degradation of ER in cancer cell lines[53,54]. Provided such mechanisms also operate in SMCs, they might explain the reduction inER expression in the intimal layer of these CHD patients.A decrease in ER was previously regarded as a risk factor for the development ofatherosclerosis. Losordo et al. showed that ER expression was reduced in atheroscleroticarteries compared with normal coronary arteries of premenopausal women [55].On the other hand, restenosis studies have shown that the local delivery of 17-estradiolinhibits neointimal proliferation without affecting endothelial repair and function [56].ER participation in SMC hyperplasia has also been observed. First, ER is involved inthe process of restenosis [57]. Likewise, the length of the nucleotide repeat regulatory region

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of the ER gene has been associated with severity of coronary artery disease in men [58]. Theauthors have suggested that carriers of the long-repeat variant have a lower expression of theER gene and that this may reduce the benefits derived from the cardiovascular protectiveeffects of the ER [58]. Accordingly, recent studies [12] also show an important role of gpERin regulating coronary artery SMC growth and promoting redifferentiation and a contractilephenotype in VSMC [59].Ultimately, this large autopsy study reports on several potentially important findings: 1)Intimal hyperplasia is a frequent finding in the coronary tree of young patients withcongenital heart disease (CHD), 2) TGF-1 and ER seem to play a major role in thisphenomenon and 3) Surgical correction of CHD is associated with further coronary vascularremodeling.The high incidence of intimal hyperplasia in patients with surgically repaired CHD islikely related to an increase in TGF-1 expression and to a decrease in ER expression in theintimal layer. Accordingly the increase in TGF-1 expression and the decrease in ERexpression might represent risk factors for the development of pre-atherosclerotic lesions incoronary arteries in CHD patients.

ConclusionThe high incidence of intimal hyperplasia in patients with surgically repaired CHD wascorrelated with an increment in TGF-1 expression and a decrease in ER expression.Augmented expression of TGF-1 and a decrease in ER expression may contribute to thedevelopment of atherosclerotic coronary artery disease in CHD patients.

AcknowledgmentsThe authors are grateful to the National Scientific and Technical Research Council(CONICET) for funding the studies mentioned in this chapter.

AbstractNew diagnostic techniques can help to understand the myocardial function incongenital heart disease. Echocardiography is a reliable, noninvasive tool to evaluateheart structure and contractile function of the left and right ventricle in children andadults. 2D color Doppler imaging of the myocardium enables rapid qualitativeassessment of wall dynamics, providing a good spatial resolution to differentiate betweenvelocity profiles of subendocardial and subepicardial layers, and allows simultaneousanalysis of various myocardial regions. Tissue Doppler velocity imaging (TDI) offers adifferent approach, as it does not rely on geometric assumptions. Possibly, the best optionfor the evaluation ventricular function is the combination of different methods: TAPSE,TDI and index of myocardial performance. Two-Dimensional (2D) Speckle-TrackingEchocardiography (STE) is a relatively new, angle independent technique that is used forthe evaluation of global and segmental myocardial function. Myocardial strain valuesregional ventricular deformation. Myocardial strain rate (SR) is a time derivative of strainand has shown to correlate linearly with left ventricle (LV) peak elastance, which is aload-independent global measure of ventricular systolic function.Conclusion: New echo technology can identify early left and right ventriculardysfunction. This may allow earlier intervention and help to avoid irreversible damage tothe myocardium in congenital heart disease.*

E-mail: ana.dedios@gmail.com.

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IntroductionEchocardiography is a reliable, noninvasive tool used for the evaluation of heart structureand function in children and adults. Many important clinical decisions are routinely based onthe absolute sizes of cardiac structures. [1] Evaluation is highly dependent on the quality ofthe measurements but also on the quality of the reference values with which thesemeasurements are compared.The American Society of Echocardiography Pediatric and Congenital Heart DiseaseCouncil recently published recommendations for quantification methods during theperformance of pediatric echocardiography. [2, 3].Unbiased reference values require appropriate normal subjects, standardizedreproducible measurements, and appropriate sample sizes. [3] In children, reference valuesare also highly dependent on accurate adjustment for body size.Conventional indices of regional and global ventricular function, defined by endocardialexcursion, are considered to be mostly load-dependent and based on geometric assumptions.

Tricuspid and Mitral Annular Plane

Systolic ExcursionThe measurement of the tricuspid and mitral annular plane systolic excursion (TAPSEand MAPSE), estimates right ventricle (RV) and LV systolic function by measuring the levelof systolic excursion of the lateral tricuspid and mitral valve annulus toward the apex in thefour-chamber view. [4, 5].These methods represent the movement of the heart from the base to the apex. Asignificant correlation was demonstrated between the TAPSE and ejection fraction (EF), asassessed by radionuclide angiography and MRI-derived volumes.Normal values increase with age during childhood until finally adult values. In adultpatients TAPSE or MAPSE > 1.8 cm suggests biventricular normal systolic function. Thisapproach is reproducible and has proven to be a strong predictor of prognosis in heartfailure when the TAPSE or MAPSE is less than 1.5 cm in the adult patient, suggesting acertain degree of systolic dysfunction in the right or left ventricle.

Tissue Doppler Imaging

Tissue Doppler imaging (TDI) is another echocardiographic technique that directlymeasures myocardial velocities (range from 0 to 20 cm/s). TDI-measured myocardialvelocities, as an index of regional ventricular function, [6] do not rely on geometricassumptions but rather are inherently one-dimensional, angle-dependent, and relatively loaddependent. Doppler gain settings also must be increased to adequately visualize TDIwaveforms.Tissue Doppler Imaging techniques: Pulsed and color TDI have been used for theassessment of myocardial function; however, both techniques have advantages and

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disadvantages. [7] With color TDI of the myocardium, we can superimpose wall motionvelocity on the two dimension (2D) echocardiographic imaging by velocity color-coding.Pulsed Doppler techniques obtain high quality Doppler signals, measure, mean andinstantaneous local acceleration, and obtain quantitative wall motion information.Nevertheless, it requires manual mapping, and it is difficult to distinguish subendocardial andsubepicardial myocardial velocities.2D color Doppler imaging of the myocardium enables rapid qualitative assessment ofwall dynamics, provides a good spatial resolution to differentiate between velocity profiles ofsubendocardial and subepicardial layers, and allows simultaneous analysis of variousmyocardial regions. However, it is limited by temporal resolution.In contrast, M mode color-coded tissue imaging: is characterized by a high spatial andtemporal resolution, although sampling is only performed along a single line.Velocities are typically are measured at the myocardium on the longitudinal axis in thefour chambers or two-chamber view to minimize the effect of cardiac translation.To study each point, the sample is placed at the level of interest and is recorded duringapnea to minimize errors. We can visualize three waveforms during the cardiac cycle (Figure1): the peak systolic wave (S wave), early diastolic wave (E wave), and end diastolic waveproduced by atrial contraction (A wave).Other recommended measurements are isovolumic contraction time (IVCT) andisovolumic relaxation time (IVRT). (Figure 1).

It is possible to calculate the Pw E/E ratio (Pw E obtained by pulse Doppler, and E obtainedby TDI), to estimate pressure in the left atrium.The pulsed Doppler early mitral inflow peak velocity E divided by TDI early diastolicmitral annular velocity (E) correlates well with pulmonary wedge pressure (PCWP).In the assessment of diastolic function, velocities typically are measured at the annuli ormyocardium in the longitudinal axis to minimize the effect of cardiac translation.

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From either the apical four chamber or two chamber acoustic windows, the region ofinterest is placed at the level of the mitral annulus on the septal, lateral, anterior, or posterioraspect. Recordings are obtained during apnea.By TDI the measured at the longitudinal axis in the four chambers view, the velocities arehigher in the base and decrease towards the apex. Systolic and diastolic velocities increasewith heart growth.In short axis views the myocardial velocities are higher at the posterior wall than at theanteroseptal wall (average value 6.31.7 cm/s versus 9.33 cm/s). [5, 8]Other recommended measurements are: the isovolumic acceleration slope (IVA): this isthe presystolic velocity slope and it is expressed in m/s2.IVA as assessed by Tissue Doppler Imaging (TDI) has been proposed as a measure of leftventricular (LV) contractility. IVA is believed to be less dependent on preload. Thismeasurement is also the less age-dependent value and is less grown-dependent thanmyocardial velocities. (Figure2).

IVA can be used as an index to evaluate the contractile function of the left ventricle. Itwas introduced as a measure unaffected by physiological changes, including changes inpreload. [8-10].Normal values for age, heart rate and body surface area (BSA) are standardized.Table 1, shows normal values for longitudinal Doppler tissue imaging (TDI): systolicwave (S), early diastolic wave (E), and late diastolic wave (A) in the left ventricle at mitralvalve annulus (MV) base level, and mid level in pediatric patients. [11]. The table also showsthe relation between shortening fraction (FA%), Tei index, and TDI systolic tissues Doppler(S) wave, Early (E) and Late (A) wave in m/s and isovolumic acceleration slope (IVA) inm/s2; with body surface at base and mid LV (statistical significance was express withp<0.05). We can also see here that the Tei index, FA%, and IVA m/s2 values were notinfluenced by body surface, while S and E waves increased with it.

Referens: FA: shortening fraction, ITei: Tei index. Base LV TDI: systolic tissues Dopplervelocity in m/s (S) and diastolic wave: Early (E) and Late (A) wave in m/s, isovolumicacceleration slope (IVA) in m/s2. The statistical significance (P) was express with p<0.05, ns:no signifative.The S wave and the E wave correlate negatively with heart rate (HR), decrease withtachycardia and increase in bradycardia; correlate positively with age, increase with age andbody surface, and have a strong correlation at the mitral, septal and tricuspid annulus. The Awave has a strong positive correlation with HR and a strong negative correlation with bodysurface and age at the tricuspid valve site only. [12] In conclusion, TDI measures changeswith aging and is influenced by anthropometry, heart rate and left ventricular growth inpediatric population. [13, 14].Such dependency of TDI-measured myocardial velocities may limit its utility as anindependent index when comparing ventricular function across differing age and loadingconditions in the pediatric population. [15, 16].In adults, TDI is a recommended component of routine echocardiography and isparticularly useful in the assessment of diastolic function of the left ventricle.Myocardial mitral annular or base segmental in systolic and early diastolic velocitieshave been shown to predict mortality or cardiovascular events. In particular, those withreduced S or E values of <3 cm/s have a very poor prognosis. [17, 18].In contrast, color and pulsed-wave TDI velocities are less accepted in pediatrics, perhapsdue to their strong age dependence in children [19].

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Myocardial velocities increase during normal childhood heart development, starting fromfetal life, and these changes vary by cardiac segment. TDI velocity maturation opens aninteresting window into the normal development of myocardial mechanics in childhood, butmakes it difficult to interpret data in an individual child. Moreover, there is a wider range ofnormal values for any given pediatric age than in adults. In the individual child, a givenmeasurement may not be very informative if the baseline is unknown. In the clinical situation,serial measurements in the same patient may in part overcome this problem. Nevertheless,TDI has been useful in the monitoring of systolic heart function in children withcardiomyopathy or after heart transplantation. Following orthotopic cardiac transplant inchildhood, patients have diminished right heart TDI velocities for reasons that areincompletely understood. [20, 21] This begins at the time of transplant and may show someimprovement during recovery, but not normalization. [22].In children with volume overload of the right ventricle due to atrial septal defects,tricuspid ring velocities are slightly higher than normal during childhood. [23]Right ventricular systolic function: Assessment of right heart function with TDIvelocities has been used widely, with a considerable body of clinical studies documenting itsutility in adults and children. Peak S velocity near the tricuspid ring is useful in theassessment of right ventricular longitudinal wall motion. The most widely studied heart defectis tetralogy of Fallot (TOF). [24, 25].The number of studies using TDI to assess right heart function in children with congenitalheart disease or pulmonary hypertension is steading increasing. TDI has been used in theassessment of RV diastolic function. [26]In Tetralogy of Fallot (TOF), tricuspid ring velocities are reduced (in presence of severeoverload caused by severe pulmonary regurgitation). Studies have shown a correlationbetween QRS complex duration on electrocardiogram and tricuspid ring velocities. Inaddition, on exercise stress testing, patients with TOF showed less contractile reserve thanhealthy controls. [27, 28].A similar pattern with diminished tricuspid ring S velocities is also seen in patients withsystemic right ventricle after atrial switch operation for transposition of the great arteries [29].TDI studies have revealed diastolic dysfunction in obese children and in cancer survivorswith preclinical anthracycline cardiomyopathy.Another potential strength of TDI velocities is the study of myocardial dyssynchronywhere color TDI is well-suited for rapid pediatric heart rates, even on fetal echocardiogram.Some studies have used peak S velocity in attempt to quantify global systolic function insingle-ventricle hearts. [30, 31] Conventional assessment of function in univentricular heartsis problematic due to the unusual configuration of these hearts. Tissue Doppler velocityimaging offers a different approach that does not rely on geometric assumptions. It representsa paradigm shift away from the familiar approach to quantify cardiac function by assessingcardiac output. [32] TDI studies give information about the properties of the heart musclerather than the pump function. However, TDI measurements should be interpreted withcaution in the single-ventricle setting as wall-motion abnormalities and abnormal loadingconditions may preclude a straightforward interpretation of the S velocity measurements. Atthe same time, for individual patients, serial measurements may still be informative in theindividual patient.Tissue Doppler echocardiography has been used in the assessment of RV diastolicfunction. [33]

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The E/E ratio, is a strong indicator of increased filling pressure in hypertrophic

cardiomyopathies. A RV E/E ratio >6 suggests a mean pulmonary pressure >10 mm Hg. [34,35].E/Eannular mitral ratio: The early diastolic velocity of the longitudinal motion of themitral annulus (E) reflects the rate of myocardial relaxation. [36] The velocity of the mitralannulus can be recorded by TDI, and this has become an essential part of evaluating diastolicfunction by echocardiography. [37, 38] In normal subjects, E increases as transmitralgradient increases with exertion or increased preload, whereas in patients with impairedmyocardial relaxation E is reduced at baseline and does not increase as much as in normalsubjects with increased preload. Lateral annulus early diastolic velocity is usually higher thanseptal annulus E. The E increases with increasing transmitral gradient in healthy individuals,so that E/E is similar at rest and with exercise (usually < 8). A decreased in E is one of theearliest markers for diastolic dysfunction and is present in all stages of diastolic dysfunction.Because E annular mitral velocity remains reduced and mitral E velocity increases withhigher filling pressure, the ratio between transmitral E and E tisular (E/E) correlates wellwith LV filling pressure or pulmonary capillary wedge pressure.If the PCWP is 20 mmHg: E/Eannular is 15.If the PCWP is normal: E/E annular is <8.Because PCWP has been shown to be a prognostic indicator in patients with heart failure(HF), it is reasonable to expect E/E to be a similarly powerful prognosticator in variouscardiac diseases. Indeed, both E/E15 and B-type natriuretic peptide 250 pg./ml havecarried independent prognostic value in patients with heart failure (HF). The independentpredictive value of E/E15 for cardiac mortality or HF hospitalization has been confirmed inpatients with LV dysfunction. [39, 40]Strengths and Weaknesses of TDI: The major strength of TDI is that it is readilyavailable and allows objective quantitative evaluation of local myocardial dynamics. Over thepast decade, this ability triggered extensive research in a variety of disease states that affectmyocardial function, either globally or regionally, as reflected by the large body of literatureinvolving this methodology. It is well established that peak tissue velocities are sufficientlyreproducible, which is crucial for serial evaluations. Also, spectral pulsed TDI has theadvantage of online measurements of velocities and time intervals with excellent temporalresolution. The major weakness of TDI is its angle dependency, as any Doppler-basedmethodology can by definition only measure velocities along the ultrasound beam, whilevelocity components perpendicular to the beam remain undetected. The best option may be tomeasure the ventricular function is the combination with different methods: TAPSE, TDI andindex of myocardial performance.

The Doppler Index of Myocardial Performance

(MPI) or TEI IndexMPI is another non-geometric index of global ventricular function [41]. It is expressed asa ratio obtained by adding the isovolumic contraction time (IVCT) and isovolumic relaxationtime (IVRT) and then dividing the result by the ejection time (ET): MPI = (IVCT +IVRT)/ET.

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The normal value for the Tei index is: <0.45 (0.39 0.05). [41] But there are somelimitations: atrial fibrillation, atrioventricular (AV) block, valvulopathies, and restrictivemyocardiopathy. There is an excellent correlation between ejection fraction (EF) and TAPSE,DTI and MPI. [42, 43]Increased TEI values correlate with increased ventricular dysfunction. It has beenestablished that MPI or TEI index is established that it is actually unaffected by heart rate,loading conditions or the presence and the severity of regurgitation. An MPI of >0.4 has100% sensitivity and negative predictive value in identifying abnormal EF.When EF is between 30-50%, MPI is near 0.6 (0.590.1), but when severe dysfunction ispresent with EF less than 30%, this value is near 1 (1.060.24). [42]The combination of TDI with MPI is the best predictor and discriminator of EF<50% bySimpsons method.Independent and Additive Prognostic Value of right ventricular systolic function andpulmonary artery pressure in patients with chronic heart failure are: right ventricular fractionejection (RVFE) by each 5 unit decrement; NYHA function class (III-IV versus II); leftventricular end systolic diameter (LVESDI) per each 5 mm increment; and mean pressurearterial pulmonary (PAP) per each 5 mmHg increment. [43]Other methods used in evaluation of left ventricle function:

The relationship between rate corrected mean velocity of circumferential fiber

shortening and systolic wall stress has been shown to be independent of heart rate,preload, and afterload.The rate of pressure development (dp/dt max) is also used as an index ofcontractility. As demonstrated by numerous studies, dp/dt max is significantlyaffected by loading conditions and cannot be used as a reliable index of contractility.[44]

Tissue Track (TT)

TT is another technique derived from color TDI and represents longitudinal displacementof atrioventricular annulus in mm.This parameter decreases in dilated myocardiopathy but is affected late when severedysfunction is established. This is also seen in surgically corrected tetralogy of Fallot withsignificant overload due to chronic pulmonary regurgitation.

Two-Dimensional (2D) Speckle-Tracking

Echocardiography (STE)STE is a relatively new, largely angle-independent technique used for the evaluation ofmyocardial function. The speckles seen in gray scale B-mode images are the result ofconstructive and destructive interference of ultrasound backscattered from structures smallerthan the ultrasound wavelength. With this technology, random noise is filtered out, whilekeeping small temporally stable and unique myocardial features, referred to as speckles.

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Blocks or kernels of speckles can be tracked from frame to frame (simultaneously in multipleregions within an image plane) using block matching and provide local displacementinformation, from which parameters of myocardial function such as velocity, strain, and strainrate (SR) can be derived. [45].

Strain Strain Rate

During the past several years, strain and strain rate (SR) imaging have emerged as aquantitative technique to accurately estimate myocardial function and contractility. [46]Strain is a dimensionless parameter representing deformation of an object, relative to itsoriginal shape. Strain is expressed as the percent (or fractional) change from the originaldimension:S=L/L0 = L-L0/L0

(1)

(1) Where S is longitudinal strain, L is absolute change in length (L), and L0 is thebaseline length.SR is the local rate of deformation or strain per unit time, which equals velocitydifference per length unit:SR=S/t= (L/L0)/t= (L/t)/L0= V/L0

(2)

(2) Where V is the velocity gradient in the segment studied.

From the above equations it can be seen that strain and SR measurements can be obtainedfrom data acquired by Doppler tissue imaging. SR is calculated from the instantaneous spatialvelocity gradient in a small myocardial segment. Integrating these SR values allowscalculation of strain.Myocardial strain is a dimensionless measure of regional ventricular deformation.Myocardial strain rate (SR), a time derivative of strain, has been shown to correlate linearlywith LV peak elastance, which is a load-independent global measure of ventricular systolicfunction. [47, 48] Reference values for longitudinal systolic strain and SR are necessary inevaluating pathologic alteration in LV function. The septal and lateral longitudinal systolicstrain defined are relatively independent of maturational changes and changing hemodynamicparameters of resting heart rate (in physiologic range) through the first 18 years of life. [49].Longitudinal Strain (septal -18.30% 6.67% and lateral -20.68% 8.08%) did notchange significantly with maturation and declining heart rate from birth to 18 years. This maypartly be attributed to the fact that LV geometry (represented by the LV length-diameter ratio)remains constant from infancy to adulthood, leading to normalized torsion [50], which isconsidered a major mechanism for the deformation of the myocardium. [51, 52].Peak strain can be measured as peak systolic strain (positive or negative), peak strain atend-systole (at time of aortic valve closure), or peak strain regardless of timing (in systole orearly diastole). The time point to be used to measure peak strain in the assessment of systolicfunction depends on the specific question one wishes to answer. [53, 54].

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Assessment of 2D strain by STE can be applied to both ventricles and atria. However,because of the thin wall of the atria and right ventricle, signal quality may be suboptimal. Incontrast, all LV segments can be analyzed successfully in most patients. Feasibility is best forlongitudinal and circumferential strain and is more challenging for radial strain. Because LVrotation increases toward the apex, it is important to standardize the apical short-axis view. Incontrast to TDI, analysis of these velocity vectors allows the quantification of strain and SR inany direction within the imaging plane. Depending on spatial resolution, selective analysis ofepicardial, midwall, and endocardial function may be possible as well.In conclusion, from a color Doppler TDI we can obtain Strain, SR and TT waves at eachpoint of interest. (Figure 3)Function parameters derived from one region of interest (yellow dot) within the samecolor Doppler data set: (A) velocity; (B) displacement; (C) SR; and (D) strain.Electrocardiogram. Opening and closing artifacts allow the exact definition of the cardiactime intervals. Note that in this case, the baseline is arbitrarily set to the curve value (redarrows) at the automatically recognized beginning of the QRS complex (red open bracket).

Strengths and Weaknesses of 2D STE:

Both TDI and STE measure motion against a fixed external point in space (i.e., thetransducer). However, STE has the advantage of being able to measure this motion in anydirection within the image plane, whereas TDI is limited to the velocity component toward oraway from the probe. This property of STE allows measurement of circumferential and radialcomponents irrespective of the direction of the beam. Note, however, that STE is notcompletely angle independent, because ultrasound images normally have better resolutionalong the ultrasound beam direction compared with the perpendicular direction. Therefore, in

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principle, speckle tracking works better for measurements of motion and deformation alongthe ultrasound beam direction than in other directions. Similar to other 2D imagingtechniques, STE relies on good image quality as well as the assumption that morphologicdetails can be tracked from one frame to the next (i.e., that they can be identified inconsecutive frames), which may not be true when out of plane motion occurs. Becausespeckle tracking relies on sufficiently high temporal resolution, TDI may prove advantageouswhen evaluating patients with higher heart rates (i.e., during stress echocardiography) or ifshort-lived events need to be tracked (isovolumic phases, diastole, etc.). Validation studies on2-dimensional speckle tracking echocardiography (2DSE) suggest that the method is reliableand angle-independent. [55, 56].Longitudinal and Circumferential Mechanics: During preejection, reshaping of LVgeometry causes simultaneous shortening and stretch of the early and the late activatedregions, respectively. Thus, shortening of subendocardial fibers is accompanied bysimultaneous subepicardial fiber stretching. Segmental stretch may also be seen in the lateactivated regions of the subendocardium, particularly near the base posterolateral region,which is the last area of the ventricle to activate. The onset of longitudinal and circumferentialshortening therefore shows substantial transmural and apex-to-base heterogeneity.Subendocardial and subepicardial layers shorten concurrently during ejection. The magnitudeof circumferential strains during ejection exceeds that of longitudinal strains. Furthermore,longitudinal and circumferential shortening strains during ejection show a small apex-to-basegradient, such that successive shortening strains are higher at apical and mid segmentscompared with the LV base. Acute ischemia produces, within a few minutes, a local reductionin myocardial contractility. In studies looking at strain and SR during coronary angioplasty,typical changes could be found that were shown to have high sensitivity and specificity forthe diagnosis of ischemia. During acute ischemic insult, there is a decrease in peak systolicstrain (longitudinal and radial) and a decrease in peak systolic SR. In addition, segmentalrelaxation is impaired, resulting in loss of the early diastolic thinning and lengthening. Theseare replaced by local early diastolic thickening and shortening, known as post- systolic strain.[53, 54] Several studies have shown that the combination of reduced peak systolic strain withsignificant increase in post- systolic strain is a highly sensitive marker for acute ischemia.

Automatic Function Imaging (AFI) or

Bidimensional Myocardial DeformationThis technique derives from speckle tracking. It is also known as non-Doppler 2D Strainimaging and is a new echocardiographic technique that allows the measurement ofmyocardial strain and strain rate. It analyzes motion by tracking speckles in the ultrasonicimage in two dimensions and requires only one cardiac cycle to be acquired. Furtherprocessing and interpretation can be done after image data acquisition.Because AFI is not based on tissue Doppler measurements, it is angle independent. 2Dstrain images are quickly achieved. This technique may prove to be of significant clinicalvalue, enabling rapid and accurate assessment of global and segmental myocardial function.The end-systolic frame is first defined in the apical long-axis (3-chamber) view, wherethe aortic valve is directly visible. Aortic valve closure time is marked. The software then

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measures the R wave to aortic valve closure time. Subsequently, the same R wave to aorticvalve closure time distance is used as a reference on the other loops. The time distance is alsochecked against the mitral valve opening, which is easily seen in any apical plane. Thisallows accurate timing of systole, diastole, and aortic valve closure on all views. [57]Within the end-systolic frames, an estimation of the LV myocardium is traced in a clickto-point approach. Subsequently, the software automatically defines an epicardial and midmyocardial line and processes all frames of the loop. Endocardial border is identified by edgedetection, based on black-and-white transition recognition on a single frame. Themyocardium is defined by empiric estimation of myocardial thickness and can then be furthercorrected by the operator. Motion is evaluated by tracking speckles (natural acoustic markers)in the ultrasonic image in two dimensions. By tracking the entire LV myocardium, the newborder is determined without the need for repeated border location by edge detection. On allapical views, end-diastolic volume, end-systolic volume and EF are calculated based on themodified Simpsons rule. Motion and velocities are then analyzed by calculating frame-toframe changes. The final result showing is a continuous cineloop, tracking the acousticmarkers and superimposing color points on the gray scale image. A visual control for theindividual tracking quality is directly performed thereafter.Tracking quality is based on several criteria:

each speckle is followed for several consecutive frames forward and backward.Return to baseline coordinates is considered evidence for adequate tracking.adjacent speckles (that are in close proximity within the tissue) are assumed to havesimilar velocities. If a significant difference in tissue velocities is detected, thesoftware rejects the tracking.the software evaluates the drift compensation that is required.

The strain at the beginning and the end of a cardiac cycle should be the same. The largerthe required drift compensation, the lower the tracking quality scores. The automaticallyobtained tracking process may be accepted or rejected by the reader.The myocardium in each of the 3 standard apical planes is automatically divided into 6segments, and the analyzed values within the middle points for all resulting 18 segments areshown as traces in specific diagrams. These diagrams can display different parameters (strain,SR, displacement, velocities), which are all derived from the instantaneous angle-independentspeckle velocities. [58] The resulting signal is a continuous tracking cineloop. (Figure 4).

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The greatest advantages of AFI are that it analyzes wall motion in real time and allows anautomatic assessment of ventricular function. It simultaneously obtains the curved anatomicalM mode and its scale deformation. (Figure 5)It also shows deformation waves in time of each region and a dotted average wave.Bidimensional myocardial deformation gives information about systolic and diastolicfunction in three dimensions: longitudinal, radial and circumferential; and it can be measuredboth regional or globally. [59]During ventricular systole, longitudinal fibers shorten towards the apex while radialfibers thicken. Circumferential fibers converge towards the center, decreasing its axis. [60]Longitudinal deformation images are acquired from apical views.Longitudinal deformation is larger in apical than in base segments. Radial andcircumferential deformation images should be achieved in transversal minor axis views. Theincidence of major events is significantly higher in patients with biventricular dysfunctionrather than in isolated left ventricular dysfunction (45% versus 11%, p < 0.0001). [61, 62]

A: Tracked apical loop with color-coding of the 6-myocardial segments. B: Average segmental straingraphically displaced. Each color line corresponds to the same color-coded myocardial segment. C:Color display of peak systolic strain. Color scale shown on the right corner. D: M mode representationof peak systolic strain. Myocardial segments are color-coded, strain color scale same as in C.Figure 5. The Left ventricular dysfunction in a patient with surgically repaired ventricular septal defect(VSD). In Apical 4-chamber quad view.

Peak strain is assessed in 16 LV segments at aortic valve closure (peak systolic strain).Peak systolic strain from each segment is average to global longitudinal strain (GLS) from a16-segment LV model.It is possible to obtain all of the following functions derived from a TDI color loop: TSI(time synchronic image), Tissue track (longitudinal movement), Strain (myocardialdeformation), Strain rate (myocardial deformation in time). Speckle tracking permits theanalysis of bidimensional myocardial deformation, as is shown in the example of a surgicallyrepaired VSD with severe biventricular dysfunction. (Figure 6).Electromechanical dyssynchrony is an important consequence of and contributor toventricular dysfunction. [63, 64] Echocardiography can be useful to assess the mechanismsunderlying mechanical dyssynchrony, to evaluate the impact of mechanical dyssynchrony onventricular function, and to try to predict the therapeutic response to cardiacresynchronization therapy (CRT).Regional bidimensional myocardial deformation represents the regional ejection fraction(EF), while end systolic global deformation represents left ventricular EF. There is asignificant correlation between apical view 4-chamber peak systolic global longitudinal strainand Magnetic Resonance Imaging left ventricular EF (in the pathologic adult population).[65].The most important benefit of STE in the pediatric age range is the angle independenceand lack of geometric assumptions. [66] Mechanical dyssynchrony has been demonstrated inseveral pediatric acquired and congenital cardiac conditions, but experience is still limited.Understanding mechanisms of electromechanical dyssynchrony by echocardiography seemspromising, at least in left bundle branch block (LBBB), but may be limited in children due tothe uncommon occurrence of LBBB in this population. [67].

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LV TorsionLV torsion is due to the contraction of subepicardial oblique fibers towards the apex witha counterclockwise rotation. In contrast, subendocardial fibers rotate clockwise.By convention, counterclockwise rotation is displayed as positive when viewed from theapex. In the normal heart, there is a wringing motion with an early counterclockwise and thenmore dominant clockwise rotation at the base, and counterclockwise rotation at the apexduring systole. [68] This motion results in a net gradient between the baseapex and it isreferred to as net LV twist and is expressed in degrees (). [69]LV torsion seems to have an important role in normal systolic function and the diastolicdetorsion allows a normal LV filling by a suction mechanism. Diminished LV detorsionwith less diastolic suction contributes to diastolic dysfunction in sick hearts.

Tetralogy of Fallot (TOF)

The Right Ventricle (RV) responds with spherical dilatation to volume over load andwith hypertrophy to pressure over load. [70] The knowledge of RV remodeling is importantfor understanding its response and discovering the mechanisms of ventricular dysfunction.TOF patients develop not only dilatation of the RV but also, to a lesser degree, of the LVand with lower EF in both cases; there is also rectification of the interventricular septum,suggesting interdependency of both ventricles.In these patients RV has an increased end diastolic area at the expense of the free wall.(Figure 7) Muscle fibers distribution generates a mid ventricular muscular waist that onlyallows ventricular dilatation in the base and apical area. [70] The interventricular septumoccupies less space and the apex of the heart becomes rounded.

A: Transversal viewB: Four chamber view.The interventricular septum occupies less space. The apex of the heart becomes rounded.Figure 7. 3D echo: TOF with right ventricle dilatation in short axis view and four-chamber view.

63 patients with severe pulmonary regurgitation after surgical correction of tetralogy of

Fallot were studied in our hospital by echocardiographic assessment of the right and leftventricular systolic function in response to volume overload. [71, 72].The median (X) age of the group was: 144y, surgical correction was done at X: 2.71y.The patients were divided into 3 groups depending on end diastolic volume overload of the

measurements, evidencing the severity of the pulmonary regurgitation overload. In the firstgroup with RV <100 ml/m2, two-dimensional speckle tracking showed only a slight alterationin right ventricle function (average -17%), with normal values in the left ventricle or minimalrepercussion.

However, when the overload increased, the dysfunction was seen first in the RV; 2Dspeckle tracking then showed left ventricular dysfunction as well, with strain and strain rateanormal in base and mid LV. Figure 10.

*Longitudinal: **Circumferential:2D speckle tracking echocardiography: (A) On the right side, longitudinal view and on the left,circumferential view in a normal child. (B) After repair of TOF: on the right, LV longitudinalstrain; on the left, circumferential view of peak strain and time to peak strain in various segments.The dotted white line in both represents the global average of the segmental strain.Figure 11. LV longitudinal and circumferential strain measured by 2D speckle trackingechocardiography.

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In this example, LV longitudinal and circumferential Strain are measured by 2D speckle

tracking. The peak strain and time to peak strain in different segments are shown.The white arrows indicate the peak strain in multiple segments.Note the lower circumferential strain in patients with TOF in the posterior and inferiorsegments as compare with the healthy patients.This was a common finding. The dotted white line represents the global circumferentialstrain (the average of the segmental strains). [73].When the overload was severe (RV more than 120 ml/m2), the left ventricle showedsignificant repercussion. (Figure 12)

In moderate overload: the dysfunction started in the RV outlet (A) with moderate alteration of the RV2D speckle tracking in four-chamber view. (B) While the left ventricle showed little repercussion in thebulls eye (C).In severe overload: the right (D) and the left ventricle (E) showed severe repercussion in the 2D speckletracking as shown in the bull eye shows (F).Figure 12. 2D speckle tracking echocardiograph: in a patients with moderate (A, B, C) and severe (D,E, F) overload secondary to pulmonary regurgitation.

The same observation of the direct relationship between the RV and the LV ejectionfraction affection due to the right overload was evidenced in 2D speckle trackingechocardiography. When the overload was severe in the RV, the dysfunction in the leftventricle was severe as well.RV end-systolic volume index <90 mL/m2 and QRS duration <140 ms are associatedwith optimal postoperative outcome (normal RV size and function), and RV ejection fraction<45% and QRS duration 160 ms are associated with suboptimal postoperative outcome (RVdilatation and dysfunction). The regional myocardial deformation may be altered and can beprospectively evaluated from echocardiography-derived speckle-tracking analysis to measuremyocardial strain and provide direct information about the contractile performance of theright ventricle. [64].RV basal wall peak diastolic velocity tended to be lower for the patients with restrictivephysiology, likely reflecting impaired relaxation of the noncompliant right ventricle.Likewise, their peak RV basal and mid wall diastolic strain rates were higher than those withnonrestrictive physiology, with values similar to those recently reported by Friedberg et al.,[65] and decreased in comparison with controls.

Use of Coronary Computed

Instituto de Cardiologa J.F.Cabral,

Department of Radiology, Corrientes, Argentina

AbstractCoronary artery anomalies are some of the most confusing, neglected topics incardiology. The occurrence of coronary artery abnormalities is reported to beapproximately 0.2% to 5.6 %. These anomalies are usually not symptomatic and have noclinical significance, although in some particular cases can be fatal. Recently CoronaryComputed Tomography Angiography, replaces the method of choice, coronary invasiveangiography, for detecting coronary anomalies, based on its ability to accurately depictthe anatomy of the heart and thorax. A useful classification it is very important tounderstand the complex topic of coronary artery anomalies (CAAs). There are four types:Anomalies of origination and course, anomalies of intrinsic coronary arterial anatomy,anomalies of coronary termination and anomalous collateral vessels. Each tipe hasdifferents items that are shown in correlative figures in this chapter. The Malignant type,it is also reported as anomalous origination of a coronary artery from the opposite sinus(ACAOS) with intussusception of the ectopic proximal vessel, which is the subgroup ofCAAs that has the most potential for clinical repercussions, specifically sudden death inthe Young. It is very important the adequate knowledge of these anomalies in order toachieve an appropriate and accurate diagnosis, that can be the key for the good prognosisof this group of patients.

E-mail: pablobayol@hotmail.com; pablobayol@gmail.com.

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IntroductionCoronary artery anomalies (CAAs) are some of the most confusing, neglected topics incardiology [1]. The occurrence of coronary artery abnormalities in the general population isreported to be approximately 0.2% to 2 % based on the adult population [2, 3]. Angelini andcoworkers [1] found a 5.6% incidence in an ad hoc study of 1950 consecutive cineangiogramsto rule out coronary artery disease. These anomalies are usually not symptomatic and have noclinical significance. Although the medical community and general public are increasinglyaware that coronary anomalies can be fatal [1]. Certain types of coronary arteryabnormalities, the ones called malignant or hemodynamically significant [4], were related tosudden death, particularly in young athletes. According to the report of the Sudden DeathCommittee of the American Heart Association, approximately 19% of sudden death inathletes may be related to these anomalies [5]. Other studies also report that sudden cardiacdeath due to coronary anomalies, especially those which course between the root of the aortaand the pulmonary artery (range from 19% to 33% in healthy young individuals) [6, 7].Coronary angiography and autopsy were used to detect coronary artery anomalies, but theseprocedures have limitations because of their invasiveness. Coronary Computed TomographyAngiography (CTA), replaces the method of choice for detecting coronary anomalies [8].Because of its ability to accurately depict the anatomy of the heart and thorax, coronary CTAhas been deemed appropriate for evaluation of coronary anomalies. In the 2010 guidelinesfrom the American College of Cardiology and American Heart Association (ACC/AHA) forthe management of adults with congenital heart disease, the use of coronary CTA is a Class Irecommendation for initial screening of congenital coronary anomalies of ectopic origin incenters with expertise in such imaging [9, 10].

DefinitionsAny anatomic or morphologic finding found in >1% of the general population is definedas normal. A normal variant describes an alternative, relatively unusual finding that isobserved in >1% of the same population [11]. An anomaly is a morphologic feature seen in<1% of the general population [11, 12]. Angelini and col. [12] concluded that acomprehensive and widely agreed-upon scheme to define and classify Coronary ArteryAnomalies should initially consider all possible coronary anatomic variations independentlyfrom the clinical and hemodynamic repercussions of individual CAAs. Such a scheme shouldinclude the normal coronary anatomy (described in terms of quantitative and qualitativecriteria), and once the normal features have been excluded, the remaining features should beconsidered to define abnormality and should be used to generate a classification order. Thefollowing criteria are proposed to define each coronary artery:1. The right coronary artery (RCA) is the vessel that provides blood flow to the rightventricular free wall. It is not essential for the posterior descending branch tooriginate from the RCA (the most common pattern) or that the ostium of the RCA belocated at the right anterior sinus of Valsalva (which is normal).

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2. The left anterior descending (LAD) artery is the vessel that provides blood flow tothe anterior interventricular septum. It is not essential for the diagonal branch tooriginate from this vessel (as is normal).3. The circumflex (LCX) artery is the vessel that provides blood flow to the free wall ofthe left ventricle, on the obtuse margin of the heart [13].

IncidenceNormal variants of coronary artery anatomy are benign entities with limited clinicalsignificance. In contradistinction, coronary artery anomalies range from benign entities tothose associated with a high risk of sudden cardiac death. In the United States, coronaryartery anomalies are the second most common cause of sudden death in competitive athletesafter hypertrophic cardiomyopathy [13]. Van Camp and coworkers [14] reported thatcoronary anomalies cause 11.8% of deaths in US high school and college athletes. Moreover,Burke and colleagues [15] reported that, in 14 to 40 year old individuals, coronary anomaliesare involved in 12% of sports-related sudden cardiac deaths versus 1.2% of nonsportsrelated deaths [16]. Recent data suggests that the prevalence of coronary anomalies in patientsthat underwent coronary CTA in different nations varies from 1.3 % in China [17] to 2.9 % inItaly [18]. The association between Coronary anomalies and Sudden Cardiac Death (SCD),has been demonstrated in retrospective cohort analyses of autopsy reports for SCDs. In acontinuous series of 6.3 million 18-year-old recruits who underwent intense military trainingfor 8 weeks, 277 deaths unrelated to trauma were identified. A review of the clinical andnecropsy charts showed that, of 64 cardiac deaths, 21 (33%) were related to AnomalousOrigination of a Coronary Artery From the Opposite Sinus (ACAOS) of the Left CoronaryArtery [6]. In a study of 134 athletes with SCD, hypertrophic cardiomyopathy was the mostcommon cause of death (36%), followed by ACAOS (13%) [4]. In a retrospective study theprevalence of CAAs in patients who underwent Coronary CTA at the Instituto de CardiologaJ.F. Cabral Corrientes Argentina was 3.2 % (42 of 1300 patients), and 2 (4.7%) correspondof left ACAOS.

ClassificationA useful classification it is very important to understand the complex topic of coronaryanomalies. The lack of a uniform classification system is due in part to the exhaustive natureof classification schemes required to encompass some of the rarer variants and also to thedifficulty of developing a system that is intuitive but still sufficiently inclusive [7]. A basicprinciple of coronary classification should be that the nature and name of a specific coronaryartery are assigned, not according to the site of origin or proximal course, but according to thedependent territory. Angelinis group proposed a comprehensive classification scheme [12].There are four types: Anomalies of origination and course, anomalies of intrinsic coronaryarterial anatomy, anomalies of coronary termination and anomalous collateral vessels. Eachtipe has differents items that are shown in correlative figures in this chapter.

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1) Anomalies of Origination and Course

Absent Left Main Trunk (Split Origination of Left Coronary Artery)The LAD and LCX arteries arise separately with no Left Main Trunk (LMT). Separateostia of the LAD and LCX artery may occur in a small percentage (0.41%) of individualswith otherwise normal anatomy [19]. (Figure 1) Although multiple ostia represent a technicaldifficulty for the angiographer, they may also allow alternate collateral sources in patientswith proximal coronary artery disease [20].

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Anomalous Location of Coronary Ostium within Aortic Root or Near Proper

Aortic Sinus of ValsalvaHigh location: The origin of either the RCA or the LCA at a point above the junctionalzone between its sinus and the tubular part of the ascending aorta (Figure 2). 6% of adulthearts were reported to be above the sinotubular junction [21]. This anomaly usually presentsno major clinical problems, but it may cause difficulty in cannulating the vessels duringcoronary arteriography. Selective catheterization of the Right Coronary Artery may beextremely difficult [22]. The location of the coronary ostium could also be low orcommissural.

Augusto Pablo Bayol

Anomalous Location of Coronary Ostium Outside Normal Coronary Aortic

SinusesThe most common anomaly of this type is the Anomalous origin of the coronary arteryfrom the pulmonary artery (ALCAPA), and is one of the most serious congenital coronaryartery anomalies. It has an estimated prevalence of one in 300,000 live births [23]. Mostaffected patients show symptoms in infancy and early childhood. Approximately 90% ofuntreated infants die in the 1st year of life, and only a few patients survive to adulthood [24].In the most common form of this disease, the LCA arises from the pulmonary artery and theRCA arises normally from the aorta (Bland-White-Garland syndrome) (Fig 3) [25]. In infants,it presents as failure to thrive, profuse sweating, dyspnea, pallor, and atypical chest pain oneating or crying. Presentation in adults is extremely rare with symptoms of ischemia,congestive heart failure, mitral regurgitation, and malignant arrhythmias leading to suddencardiac death [26]. Surgical correction is the elective treatment because uncorrected caseshave almost 90% mortality at a mean age of 35 years old [27].The coronary ostium can also be located in the right or left ventricles, and in the Aortaand or the aortas thoracic branches.

Anomalous Location of Coronary Ostium at Improper Sinus

The four recognized patterns of an anomalous origin of a coronary artery from theopposite or noncoronary sinus are (a) the RCA arising from the left coronary sinus, (b) theLCA arising from the right coronary sinus, (c) the LCX or LAD artery arising from the rightcoronary sinus, and (d) the LCA or RCA (or a branch of either artery) arising from thenoncoronary sinus. In these anomalies, the coronary ostium may be at the normal level, or theinvolved artery may have a high or low takeoff [28]. Moreover, a coronary artery arising from

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the opposite or noncoronary sinus can take any of four common courses, depending on theanatomic relationship of the anomalous vessel to the aorta and the pulmonary trunk: (a)interarterial (i.e., between the aorta and the pulmonary artery), (b) retroaortic, (c)prepulmonic, or (d) septal (subpulmonic) [29]. It is of great clinical importance which courseis taken. Although retroaortic, prepulmonic, and septal (subpulmonic) courses seem to bebenign, an interarterial course carries a high risk for sudden cardiac death [29, 30].The LCX artery is the artery that most commonly arises from a separate ostium withinthe right sinus or as a proximal branch of the RCA (approximately 0.32%0.67% of thepopulation) [31]. Several reports have shown that this anomalous LCX artery passes behindthe aortic root [32-34]; fortunately, this anomaly has not been associated with death.

The RCA arises from the left sinus of Valsalva as a separate vessel or as a branch of asingle coronary artery in 0.03%0.17% of patients who undergo angiography. The mostcommon course of an anomalous RCA arising from the left sinus of Valsalva is interarterial[32] (Figure 5); this variant can be associated with sudden cardiac death in up to 30% ofpatients [29]. It has been postulated that, when dilation of the aorta occurs during exercise, theanomalous slit-like ostium for the RCA in the left sinus becomes narrower, possibly limitingcoronary blood flow and resulting in myocardial infarction [22, 35].

The LCA arises from the right sinus of Valsalva as a separate vessel or as a branch of asingle coronary artery in 0.09%0.11% of patients who undergo angiography. Thisanomalous LCA may take a retroaortic, prepulmonic, septal (subpulmonic) or interarterialcourse [31]. An interarterial course (Figure 6), also called the malignant type, may be seen inup to 75% of patients with this anomaly [36], who are at high risk for sudden cardiac deathdue to the acute angle of the ostium, the stretch of the intramural segment, and thecompression between the commissure of the right and left coronary cusps. It is also reported

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as anomalous origination of a coronary artery from the opposite sinus (ACAOS) [12](Figure 7) with intussusception of the ectopic proximal vessel, which is the subgroup ofCAAs that has the most potential for clinical repercussions, specifically sudden deathin the Young.

Figure 7. Anomalous location of coronary ostium at improper sinus. Left Anterior Descending (LAD)Artery that arises from right anterior sinus, with anomalous course between aorta and pulmonary artery.This anomaly is also known as Coronary Artery From the Opposite Sinus (ACAOS) of the LeftCoronary Artery [6]. (A) Volume rendered 3 dimensional reconstruction, the Left Main Trunk (LMT),LAD and the Left Circumflex Artery (LCX) can be seen behind the Pulmonary Artery (PA) intransparent blue. (B) Volume rendered 3 dimensional reconstruction, the LMT, LAD and LCX) can beseen behind the PA in very transparent blue. AO: Aorta, PA: Pulmonary Artery.

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In a continuous series of 6.3 million 18-year-old recruits who underwent intense militarytraining for 8 weeks, the researchers identified 277 deaths unrelated to trauma. A review ofthe clinical and necropsy charts showed that, of 64 cardiac deaths, 21 (33%) were related toACAOS of the left coronary artery (left-ACAOS) and that no other CAAs resulted in cardiacdeath. This was the first large-scale study of CAAs in which the denominator (all candidatesat risk) was known, the setting of the clinical events was consistent (extreme physicaltraining), and all the fatal events led to necropsy studies [6].In comparison, Drory and colleagues [37] studied the incidence of CAAs in a continuousseries of 162 patients with sudden unexpected death. The patients were less than 40 years ofage and underwent routine autopsy studies in Israel, where an autopsy is obligatory in suchcases.The incidence of CAA related sudden death was 0.6% (1 of 162 cases); taken togetherwith the recent military recruit series [6], this result suggests that extreme exercise plays apowerful role in such deaths. Whereas sudden death is usually associated with extremeexercise in young adults [38], the other manifestations of ACAOS are more frequently seen inolder adults and are related to the onset of hypertension. Other authors [39] claimed thatsudden death is seen only in young patients, possibly because of progressive hardening of theaortic wall in adults.

2) Anomalies of Intrinsic Coronary Arterial Anatomy

Coronary Ectasia or AneurysmCoronary ectasia or aneurysm, (Figure 8) is described as dilation of blood vessel lumen,exceeding the diameter of the adjacent normal segment, or the dilation exceeding the largestdiameter of a coronary vessel of a given patient more than 1.5-fold. [40] Others authors [41],proposed a classification of aneurysms, according to the morphological picture and thenumber of affected arteries. As type 1 they described dilations in all 3 epicardial coronaryarteries, type 2 as dilation in 1 blood vessel only with accompanying stenosis in anothercoronary artery, and type 3 as dilation limited only to 1 artery. Tunick et al., [42] in theirwork described aneurysms as limited, unusual dilation of the coronary artery with spherical orsaccular shape.Most commonly coronary aneurysms are located in the right coronary artery, and then indecreasing order in the left descending artery, the left circumflex artery, and only exceptionally in the left main coronary artery [43]. Atherosclerosis is the main cause of theseanomalies in adults, and Kawasaki disease in children and adolescents [44]. Coronary CTAhas been shown to be highly sensitive and specific for coronary artery aneurysms. In a study[45] performed in16 adolescents and young adults with Kawasaki disease. Images were ofadequate quality for 96% of the major coronary segments, with 100% sensitivity to detectaneurysms; sensitivity was 87.5% and specificity was 92.5% for significant coronary arterystenosis.More recently, Chu et al., [46] performed a comparative study and found that CoronaryCTA was more sensitive than 2D echocardiography for identifying fusiform and distallylocated aneurysms.

Intramural Coronary Artery

Intramural coronary artery (muscular bridge), is defined as the presence of anintramyocardial segment of a major coronary artery that normally has an epicardial course[47] (Figure 9). There is some discrepancy between the prevalence of myocardial bridging atangiography (0.5%2.5%) and that at pathologic analysis (15%85%) [48]. The cause for thisdiscrepancy is presumed to be the fact that myocardial bridging often occurs without overtsymptoms, so that patients are rarely referred for coronary angiography [49]. In some cases,however, myocardial bridging is responsible for angina pectoris, myocardial infarction, lifethreatening arrhythmias, or even death [50]. The standard of reference for diagnosingmyocardial bridges is coronary angiography, at which a typical milking effect and a stepdownstep up phenomenon induced by systolic compression of the tunneled segment maybe seen [49]. In contrast, coronary CTA clearly shows the intramyocardial location of theinvolved coronary arterial segment [48]. The ECG-gated reconstruction window used in

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standard CTA of the coronary artery is usually positioned within the diastolic phase formaximal vasodilatation and minimal motion artifacts [51]. However, when there is suspicionfor myocardial bridging, it is recommended that ECG-gated reconstruction be performedduring the systolic phase as well as the diastolic phase. Comparison of the images obtainedduring the two phases will allow assessment of luminal narrowing during the systolic phase.

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3) Anomalies of Coronary Termination

Coronary Artery FistulaCoronary artery fistula is a condition in which a communication exists between one ortwo coronary arteries and either a cardiac chamber, the coronary sinus, the superior venacava, or the pulmonary artery (Figure 11).

Augusto Pablo Bayol

This condition is seen in approximately 0.1%0.2% of all patients who undergo selectivecoronary angiography [53]. It more commonly involves the RCA (60% of cases) than theLCA (40%) [54]. In less than 5% of cases, fistulas originate from both the LCA and the RCA[55]. In coronary artery fistula, the involved coronary artery is dilated because of increasedblood flow and is often tortuous to an extent determined by the shunt volume [56]. In terms ofmorphologic features, the fistula is variable at its drainage site, with either single or multiplecommunications or a maze of fine vessels that form a diffuse network, or plexus, withextensive intramural distribution. The drainage site of the fistula has a greater clinical andphysiologic importance than does the artery of origin. The most common site of drainage isthe right ventricle (45% of cases), followed by the right atrium (25%) and the pulmonaryartery (15%) [57].

DiagnosisFor several decades, premorbid diagnosis of coronary artery anomalies was made withangiography. However, it was recently reported that, among patients with anomalouscoronary arteries identified consensually with 16 -Multidectector Computed Tomography,conventional angiographic findings alone allowed correct identification of the abnormalitiesin only 53% of cases [58]. The reason for this discrepancy may be that coronary arteryanomalies are very difficult to visualize at angiography, and even if they are visualized, theircourse may be delineated inaccurately [59].In addition to coronary angiography, transesophageal echocardiography (TEE) [60, 61]also may clinically detect coronary anomalies, but this method is not totally noninvasive andis too costly for screening large populations. Transthoracic Echocardiography it is commonlyused as a routine examination, in a continuous series of 2388 transthoracic echocardiograms[62] obtained in children, 4 anomalies of coronary origination (0.17%) were found; in 1 case,a negative echocardiographic finding was followed by sudden death related to a coronaryanomaly newly found at necropsy.Another available method is the Cardiac Magnetic Resonance Imaging (MRI), whichavoids radiation and contrast agents and yields excellent images at expert centers. Indetermining coronary origination, MRI may surpass conventional angiography, especially inpatients with congenital defects. For isolated coronary anomalies, MRI is similarly successful,although series remain small. Its greatest limitation is in determining the distal coronarycourse [63]. Therefore, this technique is less helpful in evaluating fistulas, coronaryorigination outside the normal sinuses, and collateral vessels [1].Recently Coronary CTA emerged as an essential imaging tool for evaluating the coronaryarteries, CAAs are easily assessed with this modality, which, compared with conventionalangiography, offers superior definition of the ostial origin and proximal path of theanomalous coronary artery. Knowledge of the CT appearances of various coronary arteryanomalies and an understanding of the clinical significance of these anomalies are essentialfor accurate diagnosis [59] of coronary anomalies.

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ConclusionCongenital Coronary Anomalies is a rare but not as uncommon type of coronarypathology. Coronary CTA is a very useful tool in their diagnosis because of its excellentanatomical visualization capability based on volumetric 3 Dimensional reconstruction and itsimproved temporal and spatial resolution.It is very important the adequate knowledge of these anomalies in order to achieve anappropriate and accurate diagnosis, that can be the key for the good prognosis of this group ofpatients.

Intrauterine Ductus Arteriosus

AbstractThe ductus arteriosus plays a fundamental role in directing 8085% of the rightventricular output arising from the superior vena cava, coronary sinus, and a small partfrom the inferior vena cava to the descending aorta. Its histological structure ispredominantly made up by a thick muscular layer, different from the aorta and thepulmonary artery, which increases with gestational age. The fibers have a circumferentialorientation, especially at the external layers, facilitating and making effective ductalconstriction. These factors may generate lumen alterations, which may cause fetal andneonatal complications, such as heart failure, hydrops, neonatal pulmonary hypertension,and even death. Classically, maternal administration of indomethacin and/or other antiinflammatory drugs interfere in prostaglandins metabolism, causing ductal constriction.However, many cases of fetal ductal constriction, as well as of persistent neonatalpulmonary artery hypertension, remain without an established etiology, being referred asidiopathic. In recent years, a growing body of evidence has shown that herbs, fruits,nuts, and a wide diversity of substances commonly used in daily diets have definitiveeffects upon the metabolic pathway of inflammation, with consequent inhibition ofprostaglandins synthesis. This anti-inflammatory action, especially of polyphenols, wheningested during the third trimester of pregnancy, may influence the dynamics of fetalductus arteriosus flow. The aim of this review is to present these new observations andfindings, which may influence dietary orientation during pregnancy.

Paulo Zielinsky and Stefano Busato

1. Morphology and Physiology of Normal and

Abnormal Fetal Ductus ArteriosusThe ductus arteriosus originates from the distal portion of the left sixth aortic arch, whichconnects the left pulmonary artery to dorsal aorta [1]. Its histological structure is formed byan internal elastic membrane, a tunica media muscular layer and an external adventitial layer.The muscular layer is predominant, which makes the ductal structure different from aorta andpulmonary artery, and increases with gestational age. It has a circumferential orientation,mainly at the external layers, which facilitates and makes ductal constriction effective [2].The ductus arteriosus is positioned between the pulmonary artery, near the emerging leftpulmonary artery, and the aorta, at the zone of the isthmus (Figure 1). At the aorticpulmonary plan, around 80-85% of the poorly saturated blood (50% oxygen) ejected by theright ventricle into the main pulmonary artery passes through the ductus arteriosus to thedescending aorta (around 75 ml/min), and as a result will mix with the blood coming from theleft ventricle. Due to the high pulmonary vascular resistance, only 15-20% (near 15 ml/min)are directed to the lungs. Around 40-50% of the descending aorta flow passes through theumbilical arteries and returns to the placenta for hematosis. The remaining blood will nourishthe organs and the inferior body half [3].

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The ductus arteriosus shows a peculiar differentiation program in order to prepare itselffor postnatal spontaneous closure [1]. There is a relationship between gestational age and thehistological maturation of the ductus [4]. The process of fetal intimal thickening starts at thesecond trimester of pregnancy and is characteristically a continuous process. This mechanismof intimal thickening seems to be linked to prostacyclin syntase (PGI2 syntase), which has aregulating role on ductal patency [5]. During the ductus arteriosus closing there are higherPGI2 syntase levels in smooth muscle cells at the sites of intimal thickening than in otherplaces. These findings demonstrate the relationship between ductal morphology and thepresence of PGI2 syntase [6, 7]. Vascular remodelling also seems to be associated todedifferentiation of the smooth muscle cells and to apoptosis present in the areas of tunicamedia and intimal layers [8].Hemodynamic alterations during the immediate neonatal period occur at the moment ofcessation of placentary blood circulation, lung insufflation, pulmonary vasodilation andforamen ovale closure. The sudden increase in systemic vascular resistance and the decreasein pulmonary vascular resistance generate a reverse flow through the ductus arteriosus and anabrupt increase in pulmonary flow. Some minutes after birth, 90% of the blood ejected by theright ventricle is directed to the pulmonary arteries. With the decrease in pulmonary vascularresistance there is an increase in pulmonary blood flow, which culminates with ductalocclusion [9, 10]. The functional closure of ductus arteriosus is initiated by a mechanisminduced by the higher blood oxygen concentration [11]. This mechanism, albeit mediated byprostaglandins and endothelins, is intrinsic to smooth muscle cells [12]. It is a potentiallyreversible phenomenon which occurs 8-72 hours after birth, secondary to muscularconstriction. After this event, there is a remodelling of the vascular wall, with neointimalformation caused by proliferation and migration of smooth muscle cells from the tunicamedia to the subendothelial layers. This seems to be the final event of a process, whichinitiates at the second trimester of pregnancy, starting with the accumulation ofglycosaminoglycans at the subendothelial region [5]. Usually, the ductus arteriosus remainspatent for some hours or days in the neonatal period.Physiological closure of the ductus in the term neonate starts with a phase of functionalobliteration secondary to the wall vessel muscular constriction. The closure is gradual and iscompleted more frequently in 10 to 15 hours after birth[13]. Observations in neonates showthat the arterial duct starts to close at the pulmonary arterial end, and then the constrictionspreads to the aorta [14]. After completion of ductal occlusion, the arterial ligament is formed[15]. If the ductus arteriosus remains patent in a term neonate, this is considered apathological condition. The premature baby shows a delay in the remodelling process of thetunica media layer and is less responsive to oxygen, probably as a result of the immaturity ofthe structures [16, 17].Since the ductus has a predominant muscular layer, its occlusion is influenced by anumber of different constrictor and relaxing factors. Relaxing factors are prostaglandins,nitric oxide and bradycinin, which cause liberation of prostaglandins and nitric oxide.Constrictive factors are oxygen, high doses of bradycinin and the autonomic nervous system,both sympathetic and parasympathetic [14]. The vasoconstrictive effect is dose-dependent toseveral neurotransmitters, such as acetylcholine, histamine, serotonin and cathecolamins.With the increase in gestational age, the ductus becomes less sensitive to the dilating effectsand more sensitive to constrictive factors [14, 18, 19]. Production of prostaglandins isdependent of two enzymes, which act in different states, cyclo-oxygenase-1 (COX-1),

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inflammatory processes [7, 20].Prostaglandins have been extensively studied, with clear demonstration of its potentvasodilating action upon the ductus arteriosus. However, in the last years new substances withconstrictive and dilating effects on the ductus arteriosus have been described. The dilatingaction of 3- and 5- phosphodiesterase inhibitors upon fetal and neonatal ductus arteriosus inrodents have been reported [21, 22]. This effect was shown to be more potent in fetuses thanin neonates, suggesting that these substances could be useful in primary and secondary fetalductal constriction, especially in preterm fetuses when compared to term fetuses [23]. Othersubstances with dilating effect on the ductus were described, based on the knowledge of therole of endothelin receptors as messengers of postnatal ductal constriction [9, 24, 25]. It wasshown that antagonists of endothelin receptors cause potent in vitro inhibition of theconstrictive effect of cyclo-oxygenase inhibitors during fetal life, and of the postnatalphysiological ductal constriction induced by oxygen [26, 27].Among the substances with known constrictive effect upon the ductus arteriosus,indomethacin, a cyclo-oxygenase inhibitor used in the treatment of premature labor, is one ofthe most extensively studied [28-30]. Fetal ductal constriction may occur a few hours aftermaternal administration and its action may last for several weeks. For this reason, the absenceof signs of ductal constriction after 24 to 72 hours of usage does not exclude the diagnosis[28, 29, 31-33]. Ductal sensitivity to indomethacin increases with gestational age, occurringin 5-10% of fetuses with less than 27 weeks, but reaching nearly 100% after 34 weeks ofgestation [34, 35]. In addition to indomethacin, it has been shown that several other nonsteroidal anti-inflammatory drugs (NSAID), such as nimesulide [36], diclofenac [37], aspirin,matamizole, ibuprofen [38] and many others also have the potential to cause constriction ofductus arteriosus. Selective cyclo-oxygenase-2 inhibitors, such as rofecoxib [20, 38, 39], havealso shown a constrictive ductal effect on rat and sheep fetuses [40-42]. Sulindac, anotherprostaglandin inhibitor drug utilized in premature labor, was demonstrated to have a milderand more transient constrictive effect on fetal ductus than indomethacin [33]. Glucocorticoidsalso show effects upon the ductus arteriosus patency [43, 44], but the pathophysiologicmechanism involved in the alteration of ductal tonus does not seem to be the same. There isapparent reduction in the ductal sensitivity to prostaglandin E2, which may be consequent toinhibition of the enzymatic liberation of arachidonic acid from phospholipids, a step inprostaglandin synthesis preceding cyclo-oxygenase [45]. Similar to other anti-inflammatorydrugs, the ductal effect of glucocorticoid is dose-dependent [46]. Moreover, if associated withselective or non selective NSAID, glucocorticoids have a synergistic action which increasesthe frequency and severity of ductal constriction; its incidence may double, possibly due toglucocorticoids ability to decrease the ductal sensitivity to prostaglandin [20, 30]. Otherexperimentally tested substances with proven constrictive action on rat fetuses are retinoicacid [20, 30, 34, 47], antagonists of prostanoid EP4 receptors [21, 48, 49] and inhibitors ofnitric oxide synthesis (L-name) [50-53], the latter with proven effects in humans. Recently, anovel mechanism for sustaining postnatal ductal constriction induced by oxygen has beendescribed, based on activation of the enzyme Rho-kinase [54].The action of NSAID results from inhibition of prostaglandin synthesis, by inactivationof cyclo-oxygenases. COX-1 and COX-2 are enzymes involved in prostaglandin, prostacyclinand thromboxane biosynthesis[7]. This inhibitory mechanism interferes with the synthesis ofprostaglandin G2, which is a precursor of prostaglandin E2 e F2 [28, 29]. The use of anti-

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inflammatory drugs during pregnancy for the treatment of premature labor, pre-eclampsia orintrauterine growth restriction through prostaglandin biosynthesis inhibition has allowed thestudy of the relation between ductal constriction and cyclo-oxygenase inhibitors.Indomethacin is the drug with prostaglandin inhibiting action most widely reported in theliterature. Its inhibitor effect on cyclo-oxygenase is reversible, persisting until the drug isexcreted [32, 55]. The drug passage through the placentary barrier occurs freely during thesecond half of pregnancy, being minimal in early gestation [56]. The response toindomethacin is individual in each fetus, and even in a twin pregnancy only one fetus couldbe affected, which suggests differences in ductus maturation [57]. The ductus arteriosusbecomes more sensitive to indomethacin as gestational age increases, ductal constrictionoccurring in 5-10% in fetuses with less than 27 weeks, 15-20% in fetuses between 27 and 31weeks, 50% at the 32nd week and near 100% above 34 weeks. The occurrence of ductalconstriction before the 27th week is uncommon, but there are reports of cases with 22 weeks[58].As already mentioned, many other non-steroidal anti-inflammatory compounds besidesindomethacin are potentially involved in ductal constriction, such as nimesulide [36],diclofenac [37], aspirin, metamizole, ibuprofen [38], and others [59]. An experimental studyin rats has suggested a gradation in the magnitude of the action of NSAID upon the fetalductus, being the constrictive dose-dependent effect [60].Glucocorticoids are synthetic hormones which mimic endogenous cortisol actions, ahormone produced by the glomerular zone of the adrenal gland. Glucocorticoids also act onductal patency. As occurs with the majority of other anti-inflammatory substances, this effectis dose-dependent [46]. There is enzymatic liberation of arachidonic acid, blockingprostaglandin synthesis [45], and apparent reduction in sensitivity of the ductus toprostaglandin E2. Despite the tendency to premature closure of ductus arteriosus, themechanism of action seems to be related to a primary alteration of the vessel, decreasingvascular reactivity to the relaxing effects of prostaglandin E2, without altering its synthesis[40, 61]. The association of corticosteroids with indomethacin has shown a synergistic effect[62], and the incidence of ductal constriction doubles when these drugs are taken together,even though other studies have shown that the incidence of ductal constriction withglucocorticoid in isolation was similar to that of a control group [30].

2. Repercussion, Diagnosis and Management of

Premature Ductus Arteriosus ConstrictionPremature constriction of ductus arteriosus is followed by fetal hemodynamicrepercussion. The higher resistance in the ductus generates blood flow turbulence, withincrease in systolic and diastolic velocities and decrease in ductal pulsatility index. As aresult, there is dilation of the pulmonary artery, right atrium and right ventricle, right to leftbulging of the interventricular septum, tricuspid and pulmonary insufficiency and systolic anddiastolic ventricular dysfunction [36, 63].It has been demonstrated in a study in fetuses from 28 to 32 weeks of gestation afterindomethacin administration that the drug shows a reversible constrictive effect on the ductuswith significant reduction of pulsatility index and association with secondary disturbances,

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mainly in the right ventricle, as a result of the increase in afterload, observed after about 4hours, and normalization 24 hours after withdrawal of the substance. It was suggested that thehemodynamic alterations secondary to ductal constriction are right ventricular dilation andsigns of heart failure, followed by concentric hypertrophy, decrease in the right ventricularchamber caused by mass increase and left ventricular compromise. These ventricularrepercussions were more prominent in the presence of tricuspid regurgitation [64, 65]. Flowredirected through the foramen ovale results in left chambers volumetric overload [65-67].The aortic isthmus shows a rapid increase in its sectional area in response to local increasedflow [68]. This redistribution keeps peripheral perfusion and may explain the findings fromclinical experience that show that severe ductal constriction is well tolerated for some days inthe human fetus.Past experimental studies used to speculate that constriction of the ductus arteriosusresulted in an increase of the tunica media layer of pulmonary arteries and generates asecondary increase in intrauterine vascular pulmonary resistance [69]. The hemodynamicalterations in ductal constriction may be related to pulmonary vascular alterations. In the vastmajority of studies directed to increase the knowledge about fetal and neonatal pulmonaryarterial hypertension, fetal ductal constriction is the experimental model of choice. In aclassical study, administration of indomethacin to fetal lambs was followed by fetal ductalconstriction and pulmonary hypertension [70]. Blocking of prostaglandin biosynthesisprobably has a direct effect in pulmonary arterioles in mammalian fetuses [71, 72]. Thesustained increase in right ventricular afterload is capable of producing morphological,functional and hemodynamic modifications, with chronic histological and degenerativealterations of the right ventricular myocardium [73]. Severe ductal constriction may interferewith placentary flow and myocardial performance, and may lead to fetal death. If ductalconstriction is less severe or chronical, fetal pulmonary arterial hypertension is a consequenceof excessive development of the arteriolar smooth muscular layer and constriction of thepulmonary arterioles. Predominance of the increased thickness of the muscular layer and ofthe aerial pathway mass is a feature less described in neonatal pulmonary hypertensionconsequent to other causes [74, 75]. In cases related to maternal drug usage, ventriculardysfunction may reverse after its suspension. However, if this picture is not treated, it may befollowed by endocardial ischemia and right ventricular papillary muscles dysfunction, andlater on by heart failure, hydrops and potentially death [58]. Intrauterine ductal constrictionmay cause transient or permanent tricuspid regurgitation and neonatal myocardial ischemia[69, 76].In clinical practice, in cases with severe ductal constriction after prostaglandin inhibitorydrugs, the suspension of its usage may result in a decrease of ductal velocities and an increasein the pulsatility index within 24 hours, with posterior normalization of hemodynamicconsequences [55]. Mild cases may be approached with just a decrease in the administeredsubstance concentration, but in every fetus serial echocardiographic follow-up isrecommended [28].The evidence of fetal cardiac dysfunction was described as a characteristic feature of fetalclosure of ductus arteriosus [77]. In severe cases, interruption of pregnancy may be indicated,with neonatal cardiopulmonary resuscitation. The clinical course after birth depends on theseverity of intrauterine right ventricular cardiac insufficiency and to the response to elevationin pulmonary vascular resistance [78].

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Long-term prognosis is still uncertain, but when early evolution is favorable, there areusually no late complications. After the occurrence of fetal heart failure, right ventricularfunctional abnormalities may persist throughout the neonatal period, even in those patientswith a benign outcome.Utilization of echocardiographic and Doppler techniques has allowed that the diagnosisof fetal ductal constriction, formerly possible only in necropsy, could be made in prenatal life[79]. Fetuses at risk for development of premature constriction of ductus arteriosus could bemonitorized and submitted to early intervention when necessary.Echocardiographic diagnosis of fetal ductal constriction is based on the presence, at colorDoppler, of turbulent flow in the ductus (figures 2 and 3), with increased systolic velocity[SV] (higher than 1.4 m/s), increased diastolic velocity [DV] (higher than 0.30 m/s) anddecreased pulsatility index [PI] (below 2.2). In the first publications, the cutoff point for thepulsatility index was described as 1.9 [80], but more recent studies have considered asomewhat higher limit [81, 82]. The PI is independent of the ultrasound angle and is useful inthe differential diagnosis when there is increased ductal flow without concomitantconstriction. This situation may occur when the increased SV is caused by an increase in rightventricular output. The PI does not change with gestational age and should be used to definethe diagnosis [83]. When there is total occlusion of the ductus arteriosus, absence oftransductal flow is considered diagnostic. With the increase in afterload secondary to ductalconstriction, the fetal heart shows initially proliferative growing and, at later stages,hyperplasia is substituted to apoptosis and hypertrophic response [84]. There ischaracteristically an increase in right to left diameters ratio, an increase in pulmonary arteryto aorta ratio with the interventricular septum bulging toward the left ventricle [33] (figure 4).

Figure 2. Echocardiographic image with color flow mapping in a 29-week-old fetus showing ductalconstriction. There is important flow turbulence and narrowing of the sinuous ductus.

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Figure 4. 2D echocardiographic image in a four chambers view (same fetus of Figures 2 and 3). Thereis marked right to left ventricular disproportion secondary to ductal constriction.

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Right ventricular systolic and diastolic functions are impaired in fetuses with ductalconstriction, assessed by different methods [73, 79, 85]. The hemodynamic compromise isconsidered mild when there is mild or no tricuspid and/or pulmonary regurgitation, withnormal chambers diameters; moderate in the presence of tricuspid regurgitation with rightventricular dilation without hypertrophy and/or impaired contractility, and severe when thetricuspid and/or pulmonary insufficiency is important or there is functional pulmonary atresia,right ventricular dilation with ventricular parietal hypertrophy and alteration in rightventricular contractile function. The compromise is also considered severe when there is totalductal occlusion or, alternatively, in the presence of a PI lower than 1.0, associated to anydegree of hemodynamic repercussion [23, 79]. Since the constrictive effect upon the ductusarteriosus is predominantely dose-dependent [60], it is usual the resolution of hemodynamicalterations after suspension of the causing substances without development of fetal orneonatal cardiac dysfunction [33, 34, 86-88]. Even in the presence of a severe ductalconstriction after maternal utilization of drugs with prostaglandin inhibiting effect,withdrawal of their use may show reversal of the increased SV and DV within 24 hours, withimprovement of the hemodynamic alterations [33]. In some more severe cases, interruption ofpregnancy may be necessary, sometimes with immediate cardiopulmonary neonatalresuscitation. Despite not having established the association between the duration of fetalductal constriction and the prevalence and severity of neonatal pulmonary hypertension [19],it is obviously important to remove the cause as soon as possible, in order to allow earlyrecovery.The decision to interrupt pregnancy should take into account fetal pulmonary maturity,the severity of clinical and echocardiographic manifestations of ductal constriction and thepresence or not of a progressive pattern. In the immediate neonatal period, the physiologicductal closure associated to hemodynamic changes usual to this period allow normalization ofthe cardio-circulatory alterations secondary to the increased right ventricular overload.However, as already mentioned, the prolonged increase in right ventricular pressure, whentransmitted to the lungs, may cause a reactive pulmonary arteriolar vasoconstriction withsecondary pulmonary artery hypertension, which will need intensive treatment [89]. Sincepersistent pulmonary hypertension of the neonate without cardiac abnormalities occurs inapproximately 1/1000 liveborns, and around 23% of the cases do not have a known definitiveetiology, very probably many of these cases are secondary to undetected fetal prematureconstriction of ductus arteriosus [90]. Thus, ductal constriction should always be consideredan etiological possibility in "idiopathic" neonatal persistent pulmonary hypertension. Thisdisorder carries a bad prognosis and is characterized by postnatal persistence of increasedpulmonary vascular resistance, cyanosis due to right-to-left shunts through the foramen ovaleand ductus, decreased pulmonary blood flow and severe hypoxemia [91, 92]. Persistentpulmonary hypertension of the newborn has been associated to antenatal exposure to NSAID[19, 93-102], even though a recent case-control study could not confirm this risk [103]. Infetal lambs, mechanical occlusion of the fetal ductus arteriosus reproduces the hemodynamicand structural features of persistent pulmonary hypertension of the newborn. Experimentalprenatal exposition to NSAID has demonstrated alterations similar to those found in ductalconstriction, with increased thickness of the smooth muscle layer of the pulmonary arterialvasculature [29, 104-106].

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3. Anti-Inflammatory and Antioxidant Actions

of PolyphenolsPolyphenols are chemical structures present in all the superior vegetal organisms. Morethan 8000 structures are known, and they act on pigmentation, growing, reproduction andresistance of plants against diseases [107]. There are flavonoid and non-flavonoidpolyphenols.Flavonoids represent the major family and are the basic structures of tannins orproanthocyanidins. Tannins and its flavonoids are the most well-known polyphenols inalimentation, because of their presence in beer and wine, but a wide variety of polyphenolsare present in a great number of foods and beverages. Many studies have investigated thecynetic and extension of absorption of polyphenols by mensuration of plasma concentrationand urinary or plasmatic excretion [108].Flavonoids are the most abundant polyphenols in the human diet and its consumption hastriggered the interest of consumers and food industries for many reasons, but mainly becauseof their biological activity in systems relevant to human health [109]. This biological activityis related to anti-inflammatory and antioxidant effects [110], based on its interference in theinflammatory cascade, with inhibition of prostaglandin synthesis and mediation of nitricoxide synthetase [111, 112].Polyphenols with greater importance and literature references are catechins mainly ingreen and black tea, resveratrol in wine and black grape, chlorogenic acid in coffee and teasand flavonoids present in fruits and vegetables [113].The principal alimentary sources with higher concentration in polyphenols are herbalteas, mate tea, dark chocolate, fruits, natural juices, vegetables, olive and soy oils and redwine. Among fruits, the highest concentration of flavonoids is orange, red and purple grape,strawberry and other berries, black prune and its derivatives. Vegetables with higherpolyphenol purple onion concentration are purple onion, green spices, tomato and derivatives.These foods show a concentration above 30 mg of flavonoids per 100g of food, representingan amount above the 75th percentile of the USDA database [113].In recent years, many investigational studies have been trying to ascertain the realtherapeutic effect of substances found in nature and commonly used by the generalpopulation. Several of these substances presently have their anti-inflammatory andantioxidant effects [114, 115] scientifically and unequivocally demonstrated upon the chain ofproduction of oxidative stress related to inflammatory mediators such as COX-2 andprostaglandin E2, metal proteinases and others. Substances rich in polyphenols are among themost widely used for a variety of reasons, even during pregnancy. The anti-inflammatory andantioxidant effects of these substances are secondary to inhibition of the metabolic route ofprostaglandin, especially of cyclooxygenase-2, preventing the transformation of arachidonicacid into prostaglandin [20, 39, 59]. The literature reports on the mechanism of antioxidantand anti-inflammatory action of polyphenols, which are beneficial to a large portion of thepopulation, and the scientific evidence of their ethnomedicinal effect, show that a largenumber of molecules derived from functional foods and plants have been isolated and evenintroduced successfully in the international pharmaceutical industry [116]. It has beendemonstrated unambiguously that the polyphenols decrease oxidative stress (including inpregnancy) [117], plasma triglycerides and cholesterol levels [118], blood pressure [119],

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[120, 121], the consequences of gastric hypersecretion [122], the development of someneoplasms [123-125] and atherosclerosis [126, 127], the manifestations of aging [128] andAlzheimer's disease [129], and various other health problems. Polyphenols such as quercitinand kaempferol, among many others, are present in many foods and their anti-inflammatoryand antinociceptive activities have been shown to be as or more powerful than those ofindomethacin [129-131].Green tea, for example, is a compound of young leaves from the plant Camellia sinensis[132]. Approximately 30-40% of the leaves solid extract is composed of polyphenols, mainlycatechins. Among the most important catechins present in green tea are epicatechin, gallate3.epicatechin, epigallocatechin and, predominantely, gallate-3-epigallocatechin, with contains7g per 100g of dry leaves. Several in vitro studies, both in animals and in humans, havedemonstrated their antioxidant, anticarcinogenic, anti-inflammatory, probiotic andantimicrobial actions secondary to inhibition of the endogenous inflammatory response,dependent on the interference on the prostaglandin synthesis pathway [133-136]. Black teahas also showed to be rich in catechins, and the tea compound involving theaflavin has beenshown to act on nitric oxide and on the liberation of arachidonic acid. It has already beenclearly demonstrated that tea drinkers could benefit from the protective cardiovascular effectsexerted by this polyphenol-rich substance [137, 138].Resveratrol, a polyphenol compound found in grape rind, grape juice and red wine, isknown by its antioxidant, antithrombotic anti-inflammatory and anticarcinogenic actions[139]. Several studies have demonstrated the effect of resveratrol upon the nervous system, aswell as on the liver and the cardiovascular system. One of the possible mechanisms thatexplain its biological activity is related to a decrease in liberation of arachidonic acid, thusaffecting induction of COX-2, with a consequent reduction in prostaglandin synthesis [140,141].Mate tea, a typical regional beverage very rich in polyphenols, widely consumed in SouthAmerica, mainly Paraguay, Brazil, Argentina and Uruguay, is obtained from the dried andminced leaves of Ilex paraguariensis. Many studies have demonstrated its potentantineoplasic, anti-inflammatory and antioxidant effects, due to the action of its polyphenoliccompounds [142].Orange juice has been shown to have important antioxidant activity as a result of a highcontent of flavonoids, especially quercitin, and the ability of the phytochemical substance tointeract with biomembranes. It was speculated that the daily consumption of orange juicemight be useful in providing additional protection against cellular oxidation in vivo [143].Dark chocolate shows high concentration of flavonoids and has anti-inflammatoryproperties. It has been demonstrated to have an inverse association with C-reactive protein, inamounts as low as 20g every 3 days, suggesting that the regular intake of dark chocolate mayreduce inflammatory processes [144]. Since flavonoids modify the production of proinflammatory cytokines, the synthesis of eicosanoids, the activation of platelets and nitricoxide-mediated mechanisms, a growing body of evidence is available to support the potentialaction of cocoa flavonoids in inflammation [145].Many other substances rich in polyphenols present in nature commonly used in dailyroutine by the general population also have shown definite anti-inflammatory effectssecondary to inhibition of the prostaglandin synthesis pathway. Examples are boldine, withanti-inflammatory and antithermic activities [146], propolis, with anti-inflammatory action inasthmatic patients [147], passion fruit, with cytotoxic, anti-inflammatory and scar-promoting

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effects [147-149], tomato and ginseng, also with anti-inflammatory action on COX-2 [150]salvia, with anti-inflammatory effects on acute and chronic processes [151, 152], chamomile,with moderate antioxidant and animicrobial activity and significant in vitro antiplateletactions [153-155], and many others, with variable concentrations of polyphenol substancespresenting anti-inflammatory and antioxidant effects, all of them by interfering withprostaglandin synthesis.A number of foods and beverages such as herbal teas, grapes and derivatives, orange,chocolate, fruits and many others, with high concentrations of polyphenols, are freelyconsumed throughout gestation. Despite the positive effects of polyphenols in general health,as discussed in the previous sections, other studies from our group and others point towardthe indication that maternal consumption of polyphenol-rich foods in late pregnancy,specifically in the third trimester, may be harmful to fetal health, as a result of the antiinflammatory and antioxidant effects of these substances upon the ductus arteriosus, due tothe inhibition of prostaglandin synthesis [81, 156-162]. These findings will be discussed inthe next topics.

4. Role of Maternal Intake of Polyphenol-Rich

Substances upon Fetal Ductus ArteriosusAs stated, constriction of fetal ductus arteriosus is a risk factor for pulmonaryhypertension in the newborn period, with its known severe consequences. We have alreadysuggested that maternal ingestion of polyphenol-rich foods in late pregnancy, such as herbalteas, orange and grape juice, dark chocolate, coffee, berries, olive and soy oils and manyothers, could be associated to fetal ductal constriction. The rationale for understanding thebehavior of fetal ductal arteriosus flow dynamics after maternal ingestion of polyphenols inlate pregnancy is that these substances have definite anti-inflammatory and antioxidanteffects, largely reported in the literature, based on the inhibition of cyclooxygenase-2 or othercomponents of the metabolic cascade resulting in prostaglandins biosynthesis. These actionsare similar to that involved in prostaglandin inhibition caused by NSAID.The following sections intend to show the summary of the ongoing research dealing withthis issue. The majority of these experimental and clinical studies have been published andare quoted in the references.

4.1. Experimental Studies

Experimental studies to assess the fetal ductal effects of maternal consumption ofpolyphenol-rich foods utilized ewes in the last third of pregnancy (more than 120 days),corresponding to the third trimester of human gestation.The first study has shown that fetuses of ewes submitted to an experimental diet of matetea or green tea as the only source of liquid for one week developed ductal constriction, withunequivocal histological signs: right ventricular enlargement, right ventricular hypertrophyand increased avascular zone thickness at the ductal wall [163].

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The second study demonstrated that maternal exposure of green tea for one week wasfollowed by fetal constriction, with an increase in mean systolic velocity and mean diastolicvelocity, decrease of pulsatility index and increase of mean right ventricular/left ventriculardiameter ratio. Morphological repercussion was shown by dilated and hypertrophic rightventricles and increased ductal lumen avascular zone in the group exposed to green tea, butnot in those of the control group, whose mothers received only water [159].An experimental study recently submitted for publication tested the hypothesis thatmaternal exposure to a diet with a high content of polyphenols is followed by fetal ductalconstriction and by alteration of endogenous inflammatory and oxidant mediators. Sixpregnant sheep with more than 120 days of gestational age were fed for two weeks with astandardized amount of polyphenol-rich foods (basal intake + 3100 mg/day). A significantincrease of ductal systolic and diastolic velocities and a decrease in pulsatility index wasshown after 14 days of intervention when compared to the basal state, indicating fetal ductalconstriction. Total urinary polyphenol excretion increased significantly after intervention. Itshowed a decrease in lipid peroxidation, determined by plasma thiobarbituric acid reactivesubstances (TBARS) and by non-protein reduced thiols after treatment. There was an increasein enzymes catalase and glutathione peroxidase after dietary intervention. The vasoconstrictorand anti-inflammatory effects were demonstrated by a decrease in nitric oxide afterpolyphenol consumption. Oxidative stress was associated with echocardiographic parametersof ductal constriction. Moreover, ductal systolic velocity was correlated with catalase and aductal flow pulsatility index inversely with glutathione peroxidase. Ductal constriction wasalso negatively associated with inflammatory parameters, being systolic and diastolicvelocities correlated with nitric oxide, and likewise ductal pulsatility index. In addition, bothanti-inflammatory and antioxidant mechanisms (nitric oxide with glutathione peroxidase, andnitric oxide with catalase) were correlated, confirming that both effects could be attributed topolyphenols. In conclusion, elevated experimental maternal polyphenol consumption in ewesinduced fetal ductal constriction with increased urinary excretion of total polyphenols andalterations in biomarkers of oxidative stress, characterizing the antioxidant and antiinflammatory actions of polyphenols [164, 165].

4.2. Clinical Studies

4.2.1. Development and Validation of a Food Frequency Questionnaire forConsumption of Polyphenol-Rich Foods in Pregnant WomenAll clinical studies were performed to evaluate the effects of maternal intake ofpolyphenol-rich foods after the third trimester of pregnancy on fetal ductus arteriosus dependon the adequate assessment of its concentration, and there were no validated instruments toquantify total polyphenols in pregnant women. Thus, the aim of this study was to evaluate thereproducibility and validity of a food frequency questionnaire (FFQ) with 52 items, to assessthe intake of polyphenol-rich foods in pregnant women in Brazil. This cross-sectional studyincluded 120 pregnant women who participated in two-minute nutritional interviews.The intake of polyphenols estimated by the developed FFQ was compared with the average oftwo 24-h recalls (24HR), with the average intake measured by a 3-day food diary (D3days)and with the urinary excretion of total polyphenols. Analysis of the reproducibility betweenthe FFQ showed a very high correlation. A low but significant association was observed

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between the FFQ and urinary excretion, as usual in this kind of comparison. The associationbetween the dietary survey methods varied from moderate to very high. In conclusion, thisquestionnaire showed reproducibility and validity for the quantification of consumption oftotal polyphenols in pregnant women[160].4.2.2. Maternal Consumption of Polyphenol-Rich Foods in Late Pregnancyand Fetal Ductus Arteriosus Flow DynamicsWe hypothesized that polyphenols or flavonoids present in food and beveragescommonly consumed by pregnant women could influence ductal flow dynamics, probably byinhibition of prostaglandin synthesis, and thus be a risk factor for ductal constriction. Withthat in mind, we compared ductal flow behavior and right ventricular size in third-trimesterfetuses exposed, and not exposed, to polyphenol-rich foods and beverages via maternalconsumption, to test the hypothesis that maternal consumption of polyphenol-rich foodsduring the third trimester interferes with fetal ductal dynamics. In a prospective analysis,Doppler ductal velocities and right-to-left ventricular dimensions ratio of 102 normal fetusesexposed to polyphenol-rich foods (daily estimated maternal consumption above the 75thpercentile, or 1089 mg, as previously determined) were compared with 41 normal unexposedfetuses (polyphenol ingestion below the 25th percentile, or 127 mg). In the exposed fetuses,ductal velocities were higher and right-to-left ventricular ratio was higher than in unexposedfetuses. We concluded that since it was shown that polyphenol-rich foods intake in lategestation may trigger alterations in fetal ductal dynamics, changes in perinatal dietaryorientation should be recommended, with the purpose to decrease maternal polyphenolingestion [157].4.2.3. Reversal of Fetal Ductal Constriction after Maternal Restriction ofPolyphenol-Rich Foods: An Open Clinical TrialThe purpose of this study was to test the hypothesis that fetuses with constriction ofductus arteriosus and no history of maternal ingestion of NSAID, but whose mothers haveused polyphenol-rich foods (PRF) in the third trimester, show complete reversal of the ductalconstrictive effect and its hemodynamics consequences after maternal dietary interventionaimed at restriction of these substances. A controlled clinical trial of 51 third trimester fetuseswith ductal constriction with no history of NSAID intake was designed. All mothers weresubmitted to a food frequency questionnaire and were oriented to withdraw polyphenol-richfoods, being reassessed after 3 weeks. A control group of 26 third trimester normal fetuses,with no ductus arteriosus constriction, in which no dietary intervention was offered, wasreviewed after 3 weeks. After discontinuation of PRF for three weeks or more, by means of adetailed nutritional intervention, with adequate substitution of essential nutrients, 48/51fetuses (96%) showed complete reversal of ductal constriction, with decrease in mean ductalsystolic velocity, mean diastolic velocity, mean right to left ventricular dimension ratio andincrease in mean ductal pulsatility index. Median daily maternal consumption of polyphenolrich foods was 286 mg per day and decreased after orientation to 0 mg per day. In the controlgroup, there was no significant differences in median daily maternal consumption of PRF,mean ductal systolic velocity, diastolic velocity, pulsatility index and right ventricular to leftventricular diameter ratio. This behavior is similar to that already widely reported upon thewithdrawal of NSAID in fetuses with constriction of ductus arteriosus caused by those

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pharmacological agents, when there is habitual regression of the disorder. The originalconclusion of this controlled clinical trial was that reduction of maternal polyphenol intakeduring pregnancy, especially in the third trimester, is followed by complete reversal of ductalconstriction, which may reduce the risk of neonatal hypertension and influence maternaldietary habits in late pregnancy [81].4.2.4. Restriction of Polyphenols and Fetal Ductal Flow in NormalPregnancies: An Open Clinical TrialSince we had have demonstrated reversal of fetal ductal constriction after dietarymaternal restriction of polyphenol-rich foods, due to its inhibitory action on prostaglandinsynthesis, we tested the hypothesis that normal third trimester fetuses also improve ductusarteriosus dynamics after maternal restriction of polyphenols. We designed a controlledclinical trial with 46 fetuses with gestational age equal to or above 28 weeks submitted to twoDoppler echocardiographic studies with an interval of at least two weeks, being the examinersblinded to maternal dietary habits. A validated food frequency questionnaire was applied anda diet based on polyphenol-poor foods (less than 30mg/100mg) was recommended. A controlgroup of 26 third trimester fetuses was submitted to the same protocol. Mean daily maternalestimated polyphenol intake (DMPI) decreased after dietary orientation. Significant decreasesin systolic (SV) and diastolic [166] ductal velocities, and RV/LV diameters ratio, as well asan increase in ductal pulsatility index (PI) were observed. In the control group there were nosignificant differences in DMPI, mean SV, DV, PI and RV/LV ratio.This study demonstrated that, as already reported for fetuses with ductal constriction,dietary intervention for restricting the intake of foods rich in polyphenols by pregnant womenin the third trimester for a period of two weeks or more improves ductus arteriosus flowdynamics and decreases the right ventricle size in normal fetuses. Ductal constriction is anon-categorical, yes or no phenomenon, but rather a continuous spectrum with increasingseverity related to the clinical manifestations of right ventricular overload, tricuspid and/orpulmonary regurgitation and Doppler-echocardiographic findings of increased systolic andmainly diastolic ductal flow velocities, as well as a decrease of the ductal pulsatility index.Therefore, it seems logical to consider that the initial changes, even though still not filling inthe classic criteria of constriction, can develop into more serious forms, exceeding theestablished diagnostic cutoff points. The sample assessed in this study was composed ofnormal fetuses, with exclusion of those who already had a diagnosis of ductal constriction, inorder to demonstrate how the nutritional guidance can decrease the potential risk fordevelopment of the disease. This data can influence obstetric monitoring and guidance of theeating habits of pregnant women at late pregnancy [156].4.2.5. Other Studies Relating Maternal Polyphenol Ingestion to DuctalConstrictionSeveral studies in the international literature have discussed the relationship betweenidiopathic prenatal ductal constriction and maternal consumption of polyphenol-rich foods inlate pregnancy, in the absence of exposure to non-steroidal anti-inflammatory drugs [167,168]. Case reports have shown the association of severe ductal constriction withhemodynamic repercussion (hydrops, enlarged right atrium and right ventricle) to maternal

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ingestion of polyphenols, such as violet vegetable juice, prune berry [169] and chamomileherbal tea [162].Kapadia, V., et al reported a case of fetal ductal constriction related to maternalconsumption of a juice blend containing the cyclooxygenase and nitric oxide synthaseinhibitors anthocyanins and proanthocyanidins for one week in late pregnancy. After birth,the newborn developed persistent neonatal pulmonary hypertension, needing oxygen for aprolonged period [161].

ConclusionWhen the level of evidence regarding the recommendation of avoidance of polyphenolrich substances by pregnant women, at the third trimester, is critically analyzed, an importantquestion naturally arises: why not perform a randomized clinical trial to obtain the strongestpossible evidence of this action, at the apex of the pyramid? Such a study, in simple terms,would try to resolve the research problem of the value of nutritional intervention (restrictionof polyphenols in the maternal diet) against no intervention, in the presence of fetal ductalconstriction without history of prenatal exposure to NSAID. In this hypothetical trial, thestudy factor would be the restriction of maternal intake of polyphenol-rich foods in fetuseswith ductal constriction in late pregnancy and the outcome the improvement of fetalechocardiographic signs of ductal constriction - decrease is systolic and diastolic ductalvelocities, increase in pulsatility index, decrease in right to left ventricular diameters ratio andpulmonary artery to aorta dimensions ratio, of flow turbulence, septal bulging and tricuspidregurgitation. Would there be equipoise in a randomized clinical trial with the proposedintervention and outcomes [170-174]? In other words, would it be ethical to perform arandomized clinical trial to assess the benefit of polyphenol restriction in the maternal diet atthe third trimester in the presence of ductal constriction? The answer to that question,considering the conceptual model to obtain a state of equipoise, is "no"! Such a state ofequipoise needs the triangular interrelationship of the 3 points: 1) definite benefit of the studyto society; 2) doubt of the investigator about the intervention effectivity; 3) safety of all thesubjects in the two arms of the clinical trial [172, 175-178]. Even though there is a clearbenefit to society in defining if maternal nutritional intervention decreasing maternal intake ofpolyphenols in late pregnancy improves fetal ductal constriction, the two remaining points ofthe triangle of the conceptual model of equipoise are not fulfilled. The uncertainty about theeffectivity of maternal restriction of polyphenols is no longer present, based on the previouspublished studies herein disclosed and, most importantly, safety in the two arms of arandomized clinical trial in which one of them would not receive a clearly effectiveintervention cannot be established. The deleterious effects of ductal constriction upon fetalhemodynamics and the risk of pulmonary arterial hypertension secondary to this functionaldisorder are well known. There are no reports in the literature of spontaneous reversal ofductal constriction, without removal of the causal factor. How to submit the control group tothe risk of keeping the ductus constricted, with all its potential complications? In summary, arandomized clinical trial to assess the effect of maternal dietary intervention in fetuses withductal constriction, with the level of evidences today accumulated, do not fulfill the equipoiseprinciples, and for this reason cannot be considered ethical.

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The number of evidences already available recommend (Class II, level A) a note ofcaution with regard to the consumption by women in the third trimester of pregnancy of foodswith high concentrations of polyphenols, as well as non-steroidal anti-inflammatory drugs, inorder to avoid triggering constriction of ductus arteriosus, with its potential harmfulconsequences, such as fetal and neonatal heart failure and pulmonary arterial hypertension ofthe newborn.In the presence of fetal ductal constriction unrelated to exposure of NSAID, it is essentialto apply a food frequency questionnaire to assess maternal daily consumption of polyphenols,in order to program the necessary nutritional intervention.All the information disclosed in this chapter have been discussed in a review articlerecently published by the same authors [179].

Fetal Cardiac Arrhythmias:

AbstractFetal cardiac arrhythmias (FCAs) detected during a routine clinical obstetric orultrasonography examination constitute, in our experience, a relatively frequent findingand generate a marked anxiety in the family and the obstetrician. At least 2% of allpregnancies this problem is presented.In our 25-year experience (1988-2013) a total 203 FCAs was detected. 8 patients (p)(3,9%) with premature ventricular contractions; 53p (26,1%) with flutter or atrialfibrillation; 66p (32,5%) with supraventricular tachycardia; and only 2p (0.98%) withventricular tachycardia; 5p (4,5%) sustained sinusal bradycardia; 1p (0,5%) seconddegree heart block and 68p (33,5%) with complete atrioventricular block (CAVB).They manifest at any gestational age, as early as 13th week of gestation until theterm.The association with cardiac malformations was more frequently in patients withcomplete congenital heart block 31 of 68 p (45.5%). The tachycardias we found wereassociated in 6 of 129p (4, 6%).The aim of the present chapter is to help to recognize the different FACs, carry out acorrect analysis, perform an adequate diagnosis and choose the best therapeutic behaviorand follow-up. We will therefore describe the different methods of analysis of the fetalcardiac rhythm (FCR), revise their disorder patterns, and describe their therapeuticoptions and responses.Conclusion: FCAs impose an emergency for the cardiologist since they generate amarked anxiety in both the family and the obstetrician. In flutter and fibrillation as wellas in SVT the association of hydrops and/or cardiac malformation does not imply a bad

E-mail: pedro.weisburd@gmail.com.

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prognosis sign. Hospital admission should be limited to the presence of hydrops orprematurity before 26th week of gestation according to our criteria.In CAVB, the presence of hydrops, FCF< 50 bpm and/or the association tocardiopathies are of very bad prognosis. In the cases without malformation with maternalpositive antibodies, the treatment with corticoids must be performed promptly aftermaternal blood extraction. Fetal-maternal Doppler of umbilical and middle cerebralarteries gives us the possibility of ruling out hypoxic component, and it must only betaken into account that cerebral/umbilical resistance index relation must be >1 whateverthe gestational age. Doppler of ductus venosus, suprahepatic veins and umbilical veinsmust be controlled since they may allow distinguishing fetuses with higher risk ofdeveloping hydrops.

IntroductionFetal cardiac arrhythmias (FCAs) detected during a routine clinical obstetric orultrasonography examination constitute, in our experience, a relatively frequent finding in atleast 2% of all pregnancies. [1] Though most of them are benign, obstetricians and parents arefaced to an important anxiety state. They are consequently urged to have a specializedcardiologic consultation in order to characterize the type of arrhythmia present and determinethe eventual cardiac malformation.They represent almost 15% of the specific reasons of referrals in our case studies. Lessthat 10% of detected FCAs can be under potential risk to develop certain degree of fetal heartfailure (FHF), therefore, it is important to diagnose the specific type of arrhythmia, rule outany structural malformative association and determine the need for a type of intrauterinetreatment if necessary as well as the conditions for a follow-up.The Table 1 shows our 25-year experience (1988-2013) of all FCAs we detected. In thetotal number neither supraventricular extrasystoles (SVEs) nor transient sinus bradycardias(TSBs) are included since they are considered of low risk. They were only taken into accountwhen associated to supraventricular tachycardias (SVTs) and only pointed out when amalformative association is reported. Normal fetal heart rate (FHR) ranges from 100 to 180bpm during all gestation on a regular basis. We define FCAs as an alteration of the fetalcardiac rhythm manifested by: 1) the presence of irregular beats, 2) FHR greater than 180bpm sustained or not, 3) FHR lower than 180 bpm in a sustained way. They manifest at anygestational age as early as week 13 until the term, not related to pregnancy delivery or uterinecontractions. We firstly cite those most frequently diagnosed arrhythmias and then follow adecreasing order: Transient Sinus Bradycardias (TSBs) and supraventricular extrasystoles(SVEs), supraventricular tachycardias of atrial origin such as flutter and fibrillation, and, in alesser frequency, chaotic atrial tachycardias (CATs). You will find those using accessorypathways of anterograde or retrograde flow between atria and ventricles, either inside theatrioventricular (AV) node or through the AV ring, thus generating a reentry mechanism witha same atrial and ventricular frequency named as junctional supraventricular tachycardias(JSVTs). Persistent bradycardias are rarely shown such as the CAVB, atrioventricular blockof second grade, and very uncommonly permanent sinus bradycardia (PSB). Finally,tachycardias of ventricular origin (VT) are observed.The aim of the present chapter is to help recognize the different FACs, carry out a correctanalysis, perform an adequate diagnosis and choose the best therapeutic behavior andfollow-up.

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Table 1. Experience 1988-2013: PAC, Premature Atrial Contraction is not included in

We will therefore describe the different methods of analysis of the fetal cardiac rhythm(FCR), revise their disorder patterns, and describe their therapeutic options and responses. Wewill also stress the importance of arterial and venous maternal-fetal Doppler for itsevolutional follow-up.

Analysis of the FCR

The analysis of the cardiac rhythm is performed with the surface record (ECG) in theneonate obtaining the electric sequence of each beat, what makes it possible to exactlydetermine events such as the atrial electric activation (P wave) and ventricular electricactivation (QRS complex).Echocardiography was established as the main technique available for the detection,diagnosis and follow-up of FCAs. [2-4] The Movement Mode or M Mode and the PulsedDoppler enable the simultaneous record of the mechanical phenomena and arterial and venousflows which will be mainly used for their relative simplicity as an important complement forthe assessment of the aforementioned arrhythmias.The study of fetal PR (fPR) interval with the use of the intracardiac Doppler Method is ofgreat importance in the follow-up of pregnancies of mothers bearing connective tissuediseases and/or with history of children with CAVB, as well as for the analysis of sustainedsinus bradycardias (SSB).Magnetocardiography is the instrument used at present to detect and record theelectromagnetic signals related to electric phenomena of fetal heart. [5-7] This diagnosticinstrument is currently available in a few centers.

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Movement Mode (M Mode)

The M Mode allows the simultaneous record of the atrial and ventricular wall, thusextrapolating the mechanical sequence of the atrial contraction (AC) and ventricularcontraction (VC) in real time with P wave and QRS of surface ECG respectively. This allowsthe determination of an AC/VC relationship (AC/VC R) which will help define the types andbehaviors of the different FCAs.Their obtaining is simple and is performed from a cross section of the four-chambersview (4ch), placing the line of MM so as to simultaneously cross an atrium and thecontralateral ventricle, thus obtaining both contractions and its sequence (Figure 1). The useof a short-axis view cross of great vessels is another possibility of obtaining this sequence;AC is obtained followed by the aortic opening as VC. We prefer to routinely obtain theanalysis from the 4ch for its simplicity and reproducibility.

Simultaneous Venous and Arterial Doppler

The time is obtained through the simultaneous spectral Doppler record of the inlet flow ofthe left ventricle and the aortic ejection.For the Pulmonary Vein/Pulmonary Artery record we recommend to place the samplevolume with a size of at least 4 mm, outside the left atrium in the portion proximal to thelung, what is facilitated by the use of the Color Doppler. AC is identified in the venous flowas the most profound notch (near 0 line) immediately before the appearance of the arterialflow corresponding to VC (Figure 2 a and b)Doppler of Superior Vena Cava (SVC)/Aortic flows are obtained from a longitudinal ortransverse cross, locating the sample volume of the size including SVC and ascending aorta(AAo). Breathing and/or fetal movements impede correct measurements due to the variationof venous flows; therefore, we prefer to use MM for its interpretation.

Fetal PR:PR is referred to as the time interval of the cardiac cycle corresponding to the delay ofatrial-ventricular conduction between the P wave and the onset of QRS of surface ECG. Thistime is obtained from the spectral record of left ventricular inlet and aortic ejection flow. Thepulsed Doppler sample volume is placed inside the ventricular cavity near the interventricularseptum on the aortic outflow tract (Figure 3 a and b). Spectral Doppler shows the mitral flowfollowed by the aortic ejection. Time measurement is performed placing the caliper at thenotch formed by the end of E wave and the onset of A wave until the aortic ejection (Figures3 and 4).

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Figure 4. Transmital flow compared with pulsed Doppler PR interval.

The value thus obtained is of 122 +/- 10 ms with an increase of 0.4 ms for each week ofgestational age (GA) evolution and an increase of its value of 1.4 ms each 5 beats per minuteof the increase of fetal cardiac frequency (FCF). No significant differences were found withrelation to the inter sex variability.We suggest the fPR monitoring for special cases in order to precociously detect itsprolongation, establish a convenient treatment and avoid its evolution to CAVB.

ExtrasystolesSupraventricular Extrasystoles (SVEs):It is one of most frequent derivation causes generally on healthy heart, and less than 2%is associated to cardiopathies. During the examination, an intake of stimulants is manifested

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such as caffeine, cigarettes, alcohol and even substances namely mateine, cola-flavored drinksand phenols included in aromatic compounds. Fetal hypoxia can occasionally origin thesearrhythmias [8].Most of these arrhythmias sometimes disappear spontaneously when these substances areno longer used, as pregnancy progresses or in the first hours after birth. SVE is defined as thepresence of a premature contraction of atrial origin (PAC) that generates a regular or irregularalteration of FCF, generally self-limited, and even transient bradycardia of scarce duration insome cases.AC/VC R can be regular or not depending on the PAC precocity and the moment of therefractory period when it is produced. When PAC is presented in an absolute refractoryperiod, its block is generated what may cause bradycardia in high frequency cases. Thepassage depending on the frequency and types of PACs (bigeminated or trigeminated)together with different degrees of block can generate regular or irregular cardiac arrhythmias.Sometimes it is very difficult to differentiate PACs from extrasystoles of ventricularorigin, though the latter are much less frequent.The diagnosis is performed in M Mode to demonstrate the premature movement of theatrial wall, followed or not by a VC. For its correct interpretation M Mode should be utilizedas previously pointed out. (Figure 5)After a conducted PAC takes place, a fall of stroke volume develops shown through thearterial Doppler as well as in those cases where non-conducted PACs generate an increase ofstroke volume produced by an accompanying compensating pause. Only in cases where theyare very irregular and frequent, they should be closely controlled since sometimes they cancause SVT exceptions that should be treated.Figure 6 depicts a fixed bigeminated SVE that generates a ventricular bradycardia with aventricular FCF of 74 bpm due to the block of the PAC.

Figure 7 makes it possible to observe the effect of this arrhythmia over the flows of theumbilical and middle fetal arteries and over the ductus venosus. The patient continued untilthe term normalizing FCF at birth.

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Figure 8. a) M Mode blocked Premature Atrial Contraction bigeminy in a fetus with a tumor located inthe Right Atrium; b) Tumor located in the Right Atrium.

Only in 2 % (9 patients) of all cases we have detected PAC association with cardiacstructural malformation, mainly complex cardiopathies; and in one case ventricular septaldefect (VSD) was found, one associated to Pulmonary Stenosis (PS) and the other to AorticCoarctation (AoCo) and the rest with complex cardiopathies.In two cases we detected cardiac tumors in association to bigeminy PAC what induced anapparent sustained bradycardia with FCF less than 85 bpm. These tumors wererhabdomyomas and were placed at the roof of the right atrium and ventricle. (Figure 8, a andb). Arrhythmia disappeared immediately after birth.9 patients manifesting polymorphic SVE before week the 16th week of gestation withfrequent 2-second pauses showed extracardiac malformations without cardiopathies (5patients with diaphragmatic hernia, 2 patients with omphalocele, and 2 patients withanomalies of the systemic venous return (persistency of right umbilical vein to SVC andanother umbilical vein to the coronary sinus). The follow-up for these patients is performedtogether with the ultrasound scanner technician, evaluating the growth (usually not affected)and through a maternal-fetal Doppler in order to rule out the presence of disorders of theplacental flow. Fetal hypoxia might cause some of these arrhythmias, therefore the evaluationof the flows of the umbilical and middle cerebral arteries should be performed systematically.The relationship between both resistance indices known as cerebral/umbilical relationship(c/u R) should be greater than 1 independent of the gestational age [9-12]. If inverted, there isevidence of the presence of hypoxic phenomena by cerebral vasodilation, known asphenomenon of cerebral redistribution. Then values should always be taken in the wavesposterior to the post-extrasystolic wave. Venous flows such as Ductus Venosus (DV), InferiorVena Cava (IVC) or Suprahepatic Veins can be performed but they will only be irregularlyaffected and do not generate special patterns.

Ventricular Extrasystoles (VEs)

VEs are very uncommon and difficult to diagnose, sometimes they can be confused as ofsupraventricular origin. They are characterized by a premature ventricular contraction (PVC)without respecting the normal atrioventricular (AV) sequence.

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M Mode detects an AC with regular frequency and isolated PVC (Figure 9). PulsedDoppler does not add any help in the diagnosis since it fails to reliably detect AC.To differentiate VE from ventricular tachycardia, we should take into account that VEsare isolated and do not show warm-up phenomenon.In 8 patients where this disorder was detected, there was no association to structuralcardiopathy. None of our patients had any complications and at birth VE disappearedspontaneously.

TachycardiasTachycardias are defined as the presence of a FCF greater than 180 bpm that can besustained or not and may show an abrupt onset and end. They can be regular or irregulardepending on the conduction at the AV node.Generally they manifest on a healthy heart, their association to cardiopathies is veryuncommon and can potentially present risk of systemic failure and fetal death. Theirassociation to the development of hydrops is frequent (near 40% of our cases) not only in theFlutter but also in JSVT.

Flutter and Atrial Fibrillation

It is characterized by the presence of an atrial frequency of 300 to 500 bpm with avariable ventricular frequency in accordance with the conduction through the AV node to theventricles, either regular (eg.: 2/1, 3/1) or irregular.Flutter tends to show a more stable ventricular frequency than fibrillation. This is due tothe fact that its mechanism is usually the persistence of an intraatrial circular circuit,generating an incessant but regular tachycardia (Figure 10). It can cease spontaneously(Figure 11).

On the contrary, fibrillation generally involves the presence of different excitation

focuses that activate chaotically, generating a disorganization of the AC and different types ofblocks at the AV node which generates an irregular ventricular frequency.The presence or development of fetal hydrops is frequent due to the disorganization ofthe venous flow, generated by the increase of the intraatrial pressure. This generates aretrograde A wave that reaches 0 line or retrograde in the ductus venosus and in the superiorand inferior caval veins.

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The treatment can be indicated orally provided that at the diagnosis time hydrops ormarked cardiomegaly is not presented. In such a case hospitalization and endovenoustreatment (EV) are indicated.In hydropic patients a premature delivery can be induced after reversing the arrhythmia,due to the sudden absorption of the liquid of the third fetal space, and the consequentgeneration of a sudden polyhydramnios. This leads us to think of increasing the attack dose ofthe anti-arrhythmic drugs.Its association with cardiac malformations is uncommon.When analyzing the resistance of the flows of the umbilical and fetal cerebral arteries,their values should not be related to gestational age and Cerebral/Umbilical Relationship(Rc/u) should only be calculated in order to rule out fetal hypoxia signals. Figure 12 shows itseffect on the different fetal flows. The disorders produced on the venous flows are mainly theorigin of the potential development of hydrops fetalis.

Junctional Supraventricular Tachycardia (JSVT)

These are characterized by the presence of an identical Atrial and Ventricular frequency(AC/VC 1:1). They are generally greater than 220 bpm until lesser than 280 bpm. Its onsetand disappearance are sudden and can be frequently associated to extrasytoles, especially ifthey are polymorphic. (Figure 13)Its onset can be as early as week 14th week of gestational age. Figure 14 shows a SVT ina 14-week fetus that required a treatment that only responded to Flecainide, after having beentreated with Digoxin, Sotalol and Amiodarone. The mechanism of origin is the anterograde orretrograde reentry by the AV node or by accessory pathways. Most of them are on a healthyheart.To determine the type of reentry the times ranging from AC to VC and from VC to ACshould be compared. When the time from AC to VC is greater than that of VC to AC, thepresence of an antidromic pathway is determined. The slower atrial impulse travels through

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the AV node, whereas the ventricular impulse is faster from an accessory pathway. Theappearance of extrasystoles might evidence its mechanism of re-entry and generate itsinterruption.Figure 15 shows a VC-AC time lesser than AC-VC. It has a high incidence of hydropsand generally a good response to the treatment with only one drug at high doses.The same as in Flutter and fibrillation, we only indicate hospitalization when it isassociated or develops ascites or hydrops during the treatment or at the moment of diagnosis.

Figure 13. M Mode: SVT and spontaneous reversion to normal frequency.

Figure 14. a) M Mode of Supraventricular tachycardia in a fetus of 14th weeks of gestation. The timeVC-AC is 120 ms; the time AV-VC is 153 ms, b) Doppler Umbilical Artery at 250 bpm.

Fetal Cardiac Arrhythmias: Diagnosis and Treatment

Ventricular TachycardiaThey are the most uncommon tachycardias, and we could only diagnose them in twoopportunities. They are very hard to differentiate from supraventricular ones.Atrial frequency is normal, and an increase of the ventricular frequency of scant beats isonly observed, characterized by the reduction of the time between each ventricular beat as awarm-up mechanism, typical of this arrhythmia.

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Figure 18 shows a normal auricular frequency (AF) sequence until the appearance of 3VC with time shortening among them. A VT case of postnatal spontaneous disappearancewas associated to a Critical Pulmonary Stenosis that required Percutaneous BalloonValvuloplasty after birth.This arrhythmia may be accompanied by the presence of a prolonged QT Syndrome(pQTS), therefore the treatment with B-Blockers to the mother (Propranolol 80 mg 2 per day)is indicated until birth.

Treatment and Follow-up of Tachycardias

Before the presence of one of these arrhythmias the following items should be taken intoaccount: 1) Fetal hemodynamic state at the moment of the diagnosis; 2) the choice of thepathway, the response and tolerance to drugs; 3) gestational age; 4) its malformativeassociation; 5) Ultrasonography diagnosis follow-up and fetal monitoring; and 6) Arterial andVenous maternal-fetal Doppler evaluation.

Fetal Hemodynamic State

Independently of the gestational age the fetus may be compensated or with signs of fetalcardiac failure (FCF). We understand FCF as the presence or development of liquid inabdomen (ascites), thorax, subcutaneous or generalized tissue (hydrops) as well as isolatedcardiomegaly, present or not at the moment of derivation or its development during thefollow-up.The follow-up with fetal-maternal Doppler of the umbilical and fetal middle cerebralarteries (UA and MCA) should be performed. The calculation of the resistance indexcerebral/umbilical relationship must be >1 (c/u R>1). As described by Pourcelot [13] andWladimiroff [14], it must be performed in all these fetuses since it allows ruling out thepresence of fetal hypoxia signs. We indicate the carrying out of this calculation since itremains unmodified whatever the estimated FCF.The analysis of the venous flows must be taken into account for each patient since due toits disorganization it may allow identifying those with high risk to develop hydrops due to theincrease of the reversal flow during ACs.

Choice of Pathway, Response and Tolerance:

Oral administration (OA) is our first alternative at the onset of the treatment with themost elevated dose available according to the specific arrhythmia.In our opinion hospitalization is compulsory under the following conditions:Presence of fetal edema of any type at the moment of diagnosis or its development duringthe follow-up, especially with marked hydrops fetalis. When the reversal of the arrhythmia isaccomplished, the reabsorption of the fetal edema may induce a sudden polyhydramnios, thusgoing into a premature labor. This was the cause of preterm birth in three of our patients.Resistance to treatment by OA after at least 2 or 3 weeks of the onset and with two ormore drugs without having obtained a manifested improvement or at least periods withoutarrhythmia, forcing the passage to Way IV.Recurrence of arrhythmia after having been detected by either fetal echocardiography ortransabdominal fetal monitoring (in case of gestational ages over week 33)

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Gestational AgeWe consider that it is always possible to attempt first the intrauterine treatment by anypathway, at any gestational age even near term as long as there are no FCF signs and/orhypoxic suffering.

Malformative AssociationIts association with cardiopathies is very uncommon. In our experience most of themassociated lesions with those of left pathologies, aortic stenosis with double outlet of rightventricle (DORV) for instance.

Ultrasonography Follow-up and Fetal Monitoring

The ultrasonography follow-up must be performed each 48 hours in all cases untilreversal is accomplished, then continuing on a weekly basis. Conventional ultrasonographiesmust be carried out each 2 weeks in order to evaluate fetal growth and vitality and until theterm of pregnancy.The performance of the fetal monitoring (FM), that is the transabdominal record of FCR,is of great utility since it allows the record of at least 30 minutes or more. If the patient ishospitalized this can be done three or more times per day, and after reversal an ambulatorycontrol can be achieved each 48 or 72 hours.In Figure 19 it is observed a FM record of an ambulatory patient where a tachycardia wasdetected after two weeks of ambulatory treatment, forcing a dose increase.Caesarean Section is limited to those arrhythmias that did not revert with development ofhydrops or by another obstetric indication.

Arrhythmias and Anti-Arrhythmic Medication

The decision on the physician on both the drugs and the arrhythmias.Table 2 shows the doses, the estimated transplacentary passage and some of their adverseeffects.

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* Maternal/Fetal placental transfer.

* indication for fetal Complete Atrioventricular Block.

Flutter and Fibrillation

We firstly administered Digoxin at high doses (2 gm per day for 48 to 72 hours),accomplishing its reversal in almost 45% of our patients. In the event of persistence orappearance of maternal signs of bad tolerance, we have used Amiodarone OA orintravenously (IV) with excellent results. The longest time period of the treatment at highdoses (1000 mg OA per day) was of ten days.In fetuses with hydrops the firstly chosen drug was Amiodarone, starting with 1600 mgp/day IV until obtaining periods without arrhythmias recorded by the FM of at least 30minutes during hospitalization. From then onwards 200 mg/each 48 h are reduced on aregular basis until reaching the maintenance dose, passing on to OA.In 40% of the cases, 2 or more drugs were required. In 38% of the cases, hydrops weremanifested at the moment of diagnosis, reducing in all the cases and provoking a prematuredelivery in 2 patients as aforementionedIn AF Amiodarone was the first choice drug according to the previously described doseand treatment administration. Almost 50% required a second drug, coinciding with thepostnatal presence of a Chaotic Atrial Tachycardia. Ascites was present in more than 40% ofthe cases at the moment of diagnosis. In all the cases it was achieved a reversal of the prenatalarrhythmia, without fetal or neonatal deaths.SVT: In SVT the first drug of choice is generally Digoxin, followed by Amiodarone orFlecainide. (8, 15-18) Amiodarone was in most of the cases the first choice drug especiallywith the presence of hydrops. More recently and in ambulatory ways without hydrops, Sotalolwas the first drug of choice, reverting SVT in less than 24 h. Its dose was of 80 mg each 8 has attack dose, with ECG control for assessment of maternal QT. The Digoxin-Amiodaroneassociation was the most frequently used, followed by Flecainide as third choice. In somecases we associated Amiodarone and Flecainide if the arrhythmia was persistent.

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Echocardiographic control is performed each 24 hrs. until reversion of the arrhythmia,

dose reduction must be slow, especially if 2 or more drugs were required, since arrhythmiarecurrence after its reversal and during dose reduction induced dose increase and/or theaddition of a second or third drug apart from the already administered one.In a case associated to cardiac tumors, SVT was present until the age of four years undermedical treatment.No fetal death was reported for all the cases and no adverse events with relation to theirtoxicity were found. There were only two cases of premature delivery with hydrops andalready solved arrhythmia.

BradycardiasTransient Sustained Sinus Bradycardia (TSSB)TSSB is of no relevance and may take place at any gestational age. Due to their benigncondition they do not require any treatment or follow-up, though this characteristic does notminimize the important anxiety generated by the family.This is one of the most frequent causes of consultation, generally they are produced at theonset or during a routine echocardiographic study, characterized by the deceleration of FCFwith less than 100 bpm even at pauses lasting no more than 3 seconds. They immediatelyrecover when the mother is lateralized, placing her lateral decubitus or simply reducing thetransducer pressure on the abdomen.

Sustained Sinus Bradycardia (SSB)

It is defined as the presence of a constant FCF lesser than 100 bpm until the end ofpregnancy with a normal fPR, stressing a low sinus frequency. Although in some cases theycan be associated to infections or disorders caused by anesthesia.The diagnosis in M Mode shows a normal atrial-ventricular sequence (AC/VC; 1/1) andpulsed Doppler registering the inlet of left ventricle and aortic ejection, which evidence anormal fPR, thus indicating that the sequence of atrioventricular conduction is found withinnormal values. (Figure 20)It is not associated to maternal collagenopathy or any malformative pathology.Bradycardia is detected by means of a routine ultrasound scanning, has a permanentcondition and no recovery despite the reduction of the transducer pressure or the modificationof the maternal position as in the case of SB. Generally this frequency remains stable until theend of the pregnancy, forcing the delivery by cesarean section because of the impossibility ofperforming an adequate fetal monitoring.In our experience we have observed that bradycardia spontaneously disappeared in all thecases, observing HR recovery to normal values. Because some authors state that thesepatients are under risk of manifesting prolonged QT syndrome, an electrocardiographiccontrol is suggested in newborns. None of our patients reported the present or another electricanomaly after over a three-year follow-up.The Figure 21 shows the changes of maternal-fetal Doppler flows. None of them showedfetal hypoxia since c/u R was always superior to 1.

Atrioventricular (AV) Block

AV block can be classified according to its severity in three types: AV block of first andsecond-degree (incomplete ways) and third-degree or complete (CAVB). CAVB ischaracterized by a complete dissociation of AC of the ventricular ones, that is to say, there isno transmission of any stimulus from the atrium to the ventricle conditioning a normal atrialfrequency but a low ventricular one. Figure 22 Therefore, the ventricle is in charge of theescape or idioventricular pacemaker with a FCF generally lesser than 80 bpm.The diagnosis is performed with the M Mode, observing a regular AC and greater thanVC, with a 3/1 relation generally. The dissociation between AC and VC stresses the presenceof CAVB. Figure 23CAVB is a type of irreversible bradyarrhythmia because the injury of the AV node isirredeemable. It occurs approximately in one of 22,000 [19] alive newborns, with greaterincidence in prenatal life.

The cardiac output is reduced due to the lack of synchronicity of beats and bradycardia,what more often than not is translated into cardiomegaly, fetal cardiac failure and hydropsdue to the lack of synchronicity between AC and VC stresses the disorders on the venousflow.It is frequently associated to cardiac malformations or immune diseases of the maternalconnective tissue with the presence of antibodies anti RO/SSa and La/SSb. Its origin stillremains strikingly unknown.

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CAVB and Malformations

31 of 68 patients (45.5%) manifested cardiac malformations associated to block:Disorders with dextro and levo-isomerism together with univentricular hearts with severeanomalies of the vessels, Complete Atrioventricular Canal with Aortic and pulmonaryStenosis, Congenitally corrected transposition of the great vessels (CCTGV) with PulmonaryStenosis and IVC and only 3 patients with isolated CCTGV.Intrauterine mortality or within the neonatal period was of 90% within the present group.Only 3 (10%) manifesting CCTGV without IVC or PS with dextrocardia survived.

CAVB without Malformations

The presence of a CAVB without structural malformations was more frequent, 37 of 68patients (54.5%). 35 of the 37 patients (94.5%) were associated to the presence of antibodiesanti Ro/SSA and La/SSB in the maternal serum, despite the absence of symptoms or historyof maternal auto-immune diseases (Systemic Lupus Erythematosus, Sjogrens Syndrome oranother Collagenopathy). Only in 2 patients (5.5%) its etiology could not be shown or itsassociation with the prolonged QT syndrome at birth.The injury of the system of immunomediated conduction as a result of transplacentalpassage of maternal anti Ro/SSA and La/SSB antibodies would trigger the inflammation ofAV node and the myocardium of those susceptible fetuses of mothers bearing inflammatorydiseases of the connective tissue. The molecular mechanism leading to the block still remainsunknown. CAVB development takes place only in 1-2% of pregnancies with anti Ro/SSA andLa/SSB antibodies what indicated the presence of other factors that determine thedevelopment of the block. Most mothers are nonsymtomatic bearers at the moment ofdiagnosis of fetal CAVB.We have not reported AV blocks of first or second degree which may have evolvedtoward CAVB, though this was observed by other authors.As a consequence of the fibrosis in the AV node, leading to complete Block, endocardialfibroelastosis, and dilated cardiomyopathy. This would explain the improvement achieved bythe administration of corticoids (dexametasone) to the mother, evidencing in four cases thereversal of hydrops and the reduction of fetal cardiomegaly.CAVB has appeared as early as week 18.The first-degree block would precede the development of CAVB and its early detectionthrough the follow-up of fetal PR would allow preventing the development of the injury ofAV node by means of the administration of a steroid therapy, though there is no concludingevidence.

Treatment with Corticoids

When CAVB is detected and after the maternal blood extraction for the search ofantibodies, the administration of dexametasone should be performed orally. The presenttherapy could improve the survival of affected fetuses. Doses are found in table II.

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During the treatment we could reverse hydrops in 4 patients with FCF> 65 bpm. Nopositive response was found when FCF was < 50 bpm.Intrauterine mortality was produced in 8 patients (21.6%) of the present group, all ofthem showing FCF < 50 bpm and/or hydrops. 2 patients (5.5%) died during the neonatalperiod despite the placing of transient pacemakers.

ConclusionFCAs impose an emergency for the cardiologist since they generate a marked anxiety inboth the family and the obstetrician.SVE and TB do not represent any risk.In Flutter and Fibrillation as well as in SVT the association of hydrops and/and cardiacmalformation does not imply a bad prognosis sign. The treatment with drugs must start withhigh doses, either OA or IV. Hospital admission should be limited to the presence of hydropsor prematurity before week 26 according to our criteria.In CAVB hydrops, FCF< 50 bpm and/or the association to cardiopathies is of very badprognosis. In the cases without malformation with maternal positive antibodies, the treatmentwith corticoids must be performed immediate to after maternal blood extraction.Fetal-maternal Doppler of Umbilical and fetal medium cerebral arteries gives us thepossibility of ruling out hypoxic component, and it must only be taken into account that c/u Rmust be >1 whatever the gestational age.Doppler of Ductus Venosus, suprahepatic veins and Umbilical veins must be controlledsince they may allow distinguishing fetuses with higher risk of developing hydrops fetalis.

Pulmonary Hypertension and

AbstractThis chapter is an actualized review of different aspects related to pulmonaryhypertension associated with congenital heart disease. The main message that we try toconvey to the readers is the importance of early diagnosis and treatment of congenitalheart disease, to avoid pulmonary vascular disease; this means, the importance ofprevention of pulmonary vascular disease. Considering that left to right shunts are themore frequent congenital heart disease associated with pulmonary hypertension, thistopic is analyzed in wide form, from physiopathology until treatment, emphasizing theimportance of a clinical approach for early detection of Congenital Heart Disease. Ipropose a pyramidal approach to the diagnosis and treatment of congenital heart diseaseassociated with pulmonary hypertension.We emphasize that it is not correct to extrapolate the result of studies made in adultsand apply it to children. I mention that the Dana Point Classification (with the Update ofNice) is difficult to apply to children; for this reason I see that it is more applicable to usein pediatric patients the, Panama Classification: Classification of pulmonary vasculardisease in children.I give special importance to two topics: The adult with congenital heart disease andPulmonary Hypertension, including the Eisenmenger Syndrome, and pulmonaryhypertension associated with congenital heart disease at altitude. This last topic is veryimportant, considering that a great population lives at high altitudes (more than140,000,000 people); on the other hand, hypobaric hypoxia gives a special characteristicto pulmonary hypertension at high altitude, which influences biopathogenesis, clinicalaspects, diagnostic approach and treatment.

E-mail: gfdiazg50@gmail.com.

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IntroductionThe understanding pulmonary hypertension (PH) has been transformed largely in the lasttwo decades, after a growing interest and great advances made in different aspects, supportedby a better understanding of the etiopathogenesis and biopathogenesis of this condition. Thisis very different from the "shadows " that existed few years ago, as confirmed with the updateon this topic written by Marlene Rabinovitch in 1997 in which she referred to this pathologyas "a mysterious disease" [1].It is important to note that most PH studies have been carried out in adults at sea level indeveloped countries. Furthermore, the results of these studies have been extrapolated tochildren, without regard to important aspects, such as those related to the different ages of thepatients or the altitude above sea level. This last aspect is important because more than140,000,000 people in the world live over 2,500 meters above sea level (masl) [2] and a largepercentage of patients with PH live in developing countries.Within the different types of pulmonary hypertension, pulmonary hypertension associatedto congenital heart defects is included. In this group of patients it is important to note, asidefrom those already mentioned, other considerations specific to the different congenital heartdefects. This has an influence in different age groups, from the neonate to the adult, sincewith the passage of time and the advances in cardiovascular surgery, the chapter of congenitalheart defects in the adult is growing and in this context, pulmonary hypertension has animportant implication.So far, it has been established that pulmonary hypertension is an irreversible disease butin the last fifteen years there have been major therapeutic advances that have not onlyimproved the quality of life of these patients but also prolonged it. This is very different fromjust over eleven years ago, when once diagnosed with idiopathic PH, life expectancy was 2.8years for adults and 10 months for children [3].It is important to differentiate between pulmonary hypertension and pulmonary vasculardisease. In patients with pulmonary hypertension, the prevention of pulmonary vasculardisease is fundamental (see Pathophysiology), and this implies early detection. Therefore,within the process of approaching pulmonary hypertension, there should be a progressivelygrowing and evolving chapter: the prevention of pulmonary vascular disease.

DefinitionThe current definition of PH, which has not undergone many changes since the Congressof Venice (2003) is: a mean pulmonary artery pressure above 25 mm Hg with a wedgepressure or left atrial pressure less than 15 mm Hg. This implies that for the correct diagnosis,catheterization is required [4]. If only these values are considered, in patients with large left toright shunt, pulmonary pressures over these values are frequently found, without anypulmonary vascular disease. In these cases, the patient could be sent to surgery because thepatient has hyperkinetic pulmonary hypertension. This means that it is essential to take intoaccount the value of pulmonary resistance. For the definition of PH in children we follow theconsensus of the Pulmonary Vascular Research Institute (PVRI) pediatric taskforce held inPanama City in 2011. This consensus establishes criteria for the diagnosis of PH: a mean

For the purposes of this text, only pulmonary hypertension associated with congenitalheart defects will be analyzed.

Congenital Heart Defects with Associated

Pulmonary HypertensionOverviewSince 1935, [6] the severe histological changes secondary to CHD at a pulmonaryvascular level are known, which gave origin to two classical classifications (see below). Thismeans that the first knowledge of PH was based on histological studies. This knowledge hasrecently been supplemented with much research, such as the study related to the role ofelastase in the remodeling of the pulmonary vascular bed [7] and the increase of the VonWillebrand antigen component of the factor VIII originating in endothelial cells [8]. Anotherfactor to consider in patients with PH is the decreased number of pulmonary arterioles.Several classifications based on the hemodynamic situation and the natural history havebeen proposed for pulmonary hypertension associated with congenital heart defects andspecifically for those with left to right shunts [9, 10].There are five major groups of heart conditions that originate PH as seen in Table 3.

A) Left to Right Shunts

Left to right shunts are the most common heart defect group and can be divided into pretricuspid (e.g. ASD) and post tricuspid (e.g. VSD, ductus arteriosus, aortopulmonary

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window). This division is important due to the impact each of these has on pulmonarypressure, the post tricuspid defects being much more aggressive [11] (see below);nevertheless, the defect with the highest risk for developing pulmonary hypertension is thetotal atrioventricular septal defect (complete AV canal). The more severe effects on thepulmonary vascular tree due to increased pulmonary flow have been known since 1897 whenEisenmenger described the syndrome that bears his name [12, 13].Table 3. Congenital Heart Defects Associated With Pulmonary Hypertensiona) Left to right shunts.b) Cyanotic congenital heart defects with increased blood flow: TGA, Truncus Arteriosus.c) CHD originating venocapilar pulmonary hypertension:-Obstructions to the systemic blood flow: Aortic coarctation, severe aortic stenosis, etc.-Obstructions to the pulmonary venous drainage: Obstructed pulmonary venous drainage,pulmonary vein stenosis, cor triatriatum etc.-Pathologies of the mitral valve: mitral valve stenosis, etc.-Obstructions at left ventricular or atrial level: Obstructive hypertrophic cardiomyopathy, cortriatriatum, mitral supravalvular ring, etc.d) Heart defects with pulmonary circulation of systemic origin: Pulmonary branch originatedin aorta, scimitar syndrome, etc.e) Complex CHD as univentricular heart and double outlet ventricle without pulmonarystenosis, etc.

PathophysiologyTwo aspects of PH need to be considered regarding the pathophysiology:1. The direct effect of the flow per se on the pulmonary pressure considering theequation: Pressure = Flow x Resistance. This indicates that the higher the flow,the greater the pressure will be, resulting in pulmonary hypertension (PH)without necessarily causing pulmonary vascular damage; in these cases,hyperkinetic pulmonary hypertension is referred to.2. Pulmonary hypertension secondary to pulmonary vascular disease (PVD). At thispoint we make reference to PH secondary to high resistance associated withpulmonary vascular disease, a result of increased flow on the pulmonaryarterioles. It is important to remark upon the difference between pretricuspid andpost tricuspid defects. In the latter group, besides the influence of the increasedflow, the effect of systemic pressure is added, in which the shear stress graduallyrises up to produce structural damage in the arteriolar wall as can be seen inVSD, ductus arteriosus and aortopulmonary window. The pulmonary vascularremodeling that ensues, affects resistance arterioles mainly (100 to 300 mmcrs).On the other hand, in pre-tricuspid defects (e.g. ASD), flow depends on rightventricular compliance and is not influenced by systemic pressure. This is whythe vascular damage is much slower, generally appearing significantly after thesecond decade of life.

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The histological changes related with left to right shunts were analyzed by Heath andEdwards in 1958 and were the basis of their classification of 6 stages [14]. Above stage 3, theEisenmenger syndrome ensues with irreversibility as the principal characteristic. Thisemphasizes the need for early detection and treatment of these defects. Another classificationused is that of Rabinovitch [7, 15], which classifies the vascular damage in three levels and,as Haworth and Reid, takes into account the extent of smooth muscle distally [16].The severity of PH is related to increased flow and therefore with the defect size [17,18].Initially, the increased flow creates a hyperkinetic state but gradually pulmonary vasculardisease develops. The progression to PH and pulmonary vascular disease is also influenced bygenetic factors, altitude over sea level and by the genetically determined hyper-reactivity ofthe pulmonary vascular tree. Even in postnatal life, in infants with large defects, thehistological changes that normally occur after birth can be altered [19]. It is important to takeinto account that in patients with Down syndrome pulmonary vascular disease develops early,but the evidence is still controversial [20].From the pathophysiological point of view, the balance between vasoconstrictor andvasodilator substances should be considered when pulmonary hypertension is developed, witha predominance of vasoconstrictor substances, such as endothelin [21, 22].

DiagnosisIn general, early clinical diagnosis of PH is not easy, because initially it is a "silent"disease. For the diagnosis it is very important to differentiate between pulmonaryhypertension and pulmonary vascular disease, making clear that all pulmonary vasculardisease involves pulmonary hypertension, but not all pulmonary hypertension impliespulmonary vascular disease. In the context of these patients, it is essential to evaluate howcompromised the pulmonary vascular bed is.

Figure 1. Pyramidal approach proposed for the diagnosis of the patients with pulmonary hypertension:The base of the pyramid represents the clinic findings (currently neglected by technological advances)and the rest of the pyramid includes the entire set of laboratory test results. From the tip of the pyramidemerges the diagnosis of the defect(s) and hemodynamic assessment and from the analysis of these, thetherapeutic conduct is defined.

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For the study of these patients, a pyramidal approach is suggested; the base of thepyramid consists of the clinical findings and the rest of the pyramid consists of laboratory testresults (Figure 1).In this way, a comprehensive evaluation of the impact of pulmonary hypertension can bemade. Moreover, it is essential to make a comprehensive assessment of the child, looking forunderlying health conditions that may be influencing pulmonary hypertension, such as upperairway obstruction, sleep apnea, pulmonary parenchymal pathology, etc. In these cases aninterdisciplinary approach to treatment is pivotal.

Clinical FindingsLogically in pulmonary hypertension associated with congenital heart defects clinicalfindings depend largely on the underlying disease; however specific findings are related to theprogression of pulmonary hypertension. When there is significant PH, patients begin to feelprogressive fatigue with exercise and, in advanced stages, cyanosis appears with exercise,which becomes a permanent cyanosis when Eisenmenger Syndrome is established (discussedlater).Sometimes, the first sign may be a syncopal episode. On palpation, right ventriclehyperactivity intensifies with increasing pulmonary pressure and, in severe cases, evenclosure of the pulmonary valve is palpable.Regarding cardiac auscultation, it is important to analyze the 2nd heart sound; initially apermanent split of the second sound is evident, but with increasing pulmonary hypertension,the pulmonary component is intensified and it appears to be a unique and intensive secondsound. As pulmonary hypertension progresses, the murmur of VSD or ductus disappears anda mild diastolic decrescendo murmur (Graham Steel murmur) appears at the left upper thirdof the sternal border, which indicates that there is severe pulmonary hypertension; most likelyassociated to severe pulmonary vascular disease [17].In patients with severe pulmonary hypertension, arrhythmias and right ventricular failuremay occur, indicating a poor prognosis.

ElectrocardiogramThe electrocardiogram findings will also be associated to the underlying heart defect. Forexample in large VSDs, when there is hyperkinetic pulmonary hypertension, thecharacteristic sign of biventricular growth, the Katz Wachtel sign is positive: Wide biphasicRS in three leads (generally V2, V3 and V4 or between V2-V5) with R+S > 45 mm [23, 24](Figure 2A).When pulmonary hypertension is severe enough, a significant right ventriculardominance begins to appear with right axis deviation and R on the right precordial leads. Apeaked P in D2 can be found due to right atrial enlargement and diminished reduction ofleft ventricular forces appear (Figure 2B).

Pulmonary Hypertension and Congenital Heart Diseases

Chest X- RayUsually in large left to right shunts, severe cardiomegaly with biventricular and leftatrium enlargement is initially evident, with increased pulmonary flow (Figure. 3A). Aspulmonary vascular disease progresses, there is a decrease in the size of the cardiac silhouetteand pulmonary flow, and the pulmonary trunk and central pulmonary arteries becomeprominent. When there is severe pulmonary vascular disease, as in Eisenmenger Syndrome,progressive decrease in the blood flow is observed in the periphery [17] (Figure 3B).

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Figure 3A. Chest X-ray of a child with VSD and hyperkinetic pulmonary hypertension showing severecardiomegaly and increased pulmonary flow. A huge left atrium is shown.

Figure 3B. Chest X ray of a 14-year-old girl with Eisenmenger syndrome. Note that there is no"cardiomegaly", however there is persistent right ventricular growth, significant prominence of thepulmonary trunk and central pulmonary arteries with hypoflow seen in the periphery.

EchocardiographyEchocardiography is essential for the initial diagnosis and monitoring of patients withPH. In this group of patients (congenital heart defects and PH), it allows the identification ofthe characteristics of the defect, but the main drawback is that this exam is operator-

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dependent. For this reason, cardiac catheterization is essential for a definitive diagnosis andcomplete hemodynamic evaluation. Furthermore, for the evaluation of pulmonary pressure byechocardiography, it is important to achieve an ideal registry of the tricuspid insufficiency jetto apply Bernoulli's equation (gradient = velocity2 x 4). The pressure of the right atrium mustbe added to this gradient, a topic of debate. It should be considered that the value that is addedshould increase with the severity of the pulmonary hypertension. In severe cases, anacceptable value is 10 mm Hg.Pulmonary pressure in post tricuspid defects can also be evaluated through theinterventricular pressure gradient, in the case of VSD, or aortopulmonary pressure gradient, inthe case of the aortopulmonary window or ductus arteriosus, by subtracting this pressuregradient from the systemic pressure recorded simultaneously. It is important to emphasize theregistration of the optimal curve of the tricuspid regurgitation jet or the defect. Severaloptimal measurements are recommended (Figure 4). Keep in mind that in young children thecurves are often not easy to record if the patient is irritable or constantly moving; in that casethe patient must be reassured. When pulmonary insufficiency exists, the pulmonary diastolicpressure can be assessed with reference to the end of the recorded curve and adding the rightatrial pressure, while looking for an optimal registration of the curve.

Figure 4. Echocardiogram of a child with severe pulmonary hypertension. An excellent curve of thetricuspid regurgitation is shown.

Besides pulmonary pressure quantification, it is important to assess the right ventricular

function, TAPSE, inferior vena cava collapse, morphology of the left ventricle, size of theright atrium, displacement of the atrial septum to the left, and flow through any shunts. Theassessment of right ventricular function is very important, but given the geometry of the rightventricle, there is controversy about the reliability regarding the accuracy of the assessment ofright ventricular function by echocardiography; assessment by Nuclear Magnetic Resonanceis more accurate. An attempt to evaluate different parameters has been made, including right

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ventricle/left ventricle ratio, tissue Doppler, TEI index and the flattening of theinterventricular septum, which is valued very well in short axis. In severe cases, the leftventricular geometry is altered, compromising the filling of the left ventricle and paradoxicalmovement of the interventricular septum can be found. In the most severe cases, a pericardialeffusion can be found which has been associated with poor prognosis. With the analysis of thedifferent parameters, the dysfunction of the right ventricle can be defined. Another even moredifficult and less reliable aspect is the evaluation of pulmonary resistance [25-28].In conclusion the echocardiographic evaluation of patients with pulmonary hypertensionis very important, but their study is difficult and requires sufficient time to achieve an idealassessment of the heart disease, pulmonary pressure, and right ventricular function. Thesedifficulties have led to define the role of echocardiography as essential for the detection,screening, and monitoring of patients, but for an accurate diagnosis, cardiac catheterization isrequired as previously stated.

BiomarkersBiomarkers play an important role in the evaluation of pulmonary hypertension [29,30],with brain natriuretic peptide (BNP) considered the principal biomarker in clinical practice[31]. This marker is increased when pulmonary hypertension is significant, especially whenpatients are clinically decompensated. When the patient is compensated with medicaltreatment, BNP decreases because BNP does not assess pulmonary pressure but thehemodynamic repercussion of pulmonary hypertension. One drawback of BNP is that anaccurate cutoff for sensitivity and specificity has not been established. In 52 patients withpersistent pulmonary hypertension of the newborn, a specificity of 87% and sensitivity of76% was found for a value of 267 pcgr/dl. In the control group of healthy newborns, the valuewas under 20 pcgr/dl. The presence of circulating endothelial cells is another marker that isunder research [32].

Cardiac CatheterizationUndoubtedly, cardiac catheterization is the gold standard for PH evaluation and allpatients, suspected of significant pulmonary hypertension, require cardiac catheterization. Inthis moment, it is important to mention the current trend is the early correction of cardiacdefects. If there are no important findings of pulmonary hypertension, with noninvasivediagnosis, surgery can be performed without the need for catheterization [33]. Cardiaccatheterization allows us to specify the details of the heart defect and assess not only thefeatures of the malformation and the pulmonary pressure, but also the severity of pulmonaryvascular disease. In children, it is very important to analyze the type of sedation for thecatheter study since sedation and anesthesia can originate systemic hypotension, and certainlythe calculation of resistances and pressures will be distorted. Furthermore, sedation oranesthesia in patients with severe pulmonary hypertension implies a risk factor [34, 35]. It isnecessary not only to calculate the pulmonary pressure and pulmonary resistance but also toconsider the relationship of pulmonary resistance to systemic resistance and the ratio of

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pulmonary and systemic pressures. For these calculations, the use of oxygen consumption isideal but is not available in all catheterization laboratories. The application of the Fickprinciple is an appropriate method in such cases [33].As mentioned in the definition, when dealing with large left to right shunt defects,pulmonary pressures may be elevated to systemic or close to systemic levels withoutnecessarily indicating inoperability, as is the case of hyperkinetic pulmonary hypertension.Therefore it is essential to consider pulmonary vascular resistance in the assessment. Inpatients with significant hypertension and elevated pulmonary resistance, the pulmonaryvascular bed reactivity test should be applied to determine the extent of vascular compromise.Nitric oxide, oxygen or both, are often used, but adenosine or prostacyclin might be useful aswell. It should be noted that in altitude by hypobaric hypoxia, oxygen plays a pivotal role forthe pulmonary vascular reactivity test, (see below). The test is considered positive when thereis a 20% decrease in pulmonary vascular resistance compared to baseline.

Magnetic Resonance Image and

Computed TomographyDiagnostic images play an important role in the evaluation of patients with pulmonaryhypertension. Magnetic resonance imaging provides more accurate right ventricular functionassessment than echocardiography [36-38], which is pivotal before any surgical procedure.Computed tomography is useful in pulmonary vascular bed assessment to rule out intrinsicpulmonary disease as a cause of pulmonary hypertension. In adults with congenital heartdefects and pulmonary hypertension, it is essential to evaluate the pulmonary vascular bedsince pulmonary thrombosis is a common cause of it [39].

Six-Minute WalkAlthough it seems difficult to apply in children, the six-minute walk test is evolving as acardiovascular performance test, especially in children above 4 years old. There is growingexperience in its application in children [40, 41] and there are already reference valuesavailable [42].

Lung BiopsyPreviously lung biopsy was used to assess pulmonary vascular disease but its use isdecreasing, considering that a lung biopsy sample can be taken from a place with a normalpulmonary vascular bed or one not severely affected. However it continues to have animportant role when studied by very experienced professionals or for research studies.Moreover, lung biopsy studies have made large contributions to the study of patients withpulmonary hypertension but there are important limitations [7, 15, 43, 44].

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Therapeutic ApproachIn patients with pulmonary hypertension associated with congenital heart defects it isimportant to differentiate between pulmonary hypertension and pulmonary vascular disease.The best therapeutic approach for pulmonary hypertension with CHD is the early detectionand treatment of CHD to avoid the remodeling of the pulmonary vascular tree [7] in order toprevent pulmonary vascular disease, as can be seen in Eisenmenger Syndrome. If CHD aredetected and corrected opportunely, the Eisenmenger Syndrome would eventually become apart of pediatric cardiology history.In the treatment of patients with severe pulmonary hypertension secondary to congenitalheart defects, some aspects related with the operability of patients should be noted [45,46].According to the 2013 Nice Task Force recommendations (unpublished data), patients are fitfor surgical procedures if pulmonary resistance is below 4 WU/m2. On the other hand, whenpulmonary resistance is above 8 WU m2, surgery is precluded. There is a grey zone between4 and 8 WU/m2, a clinical scenario where the decision is not easy. In this type of borderlinepatients we must resort to other clinical and laboratory procedures, including the prolongedhyperoxia test (especially for patients living at an altitude of more than 2,500 meters abovesea level, see below).

Pharmacological Treatment ofPulmonary HypertensionMark Humbert described three lines of treatment for patients with pulmonaryhypertension, according to the pathophysiology of the disease [47,48]: the use of prostacyclinand its analogues, endothelin inhibitors such as Bosentan, Ambrisentan, and Maticentan (notyet available in the market) [49], and the use of the nitric oxide pathway, which increasescGMP, such as fosfodiasterase 5 inhibitors (Sildenafil) and Riociguat [50].The major drawback of prostacyclin analogues is the administration route (intravenous),since the catheter is associated with complications that put the patients at risk and is difficultfor children to tolerate. This is why its use is not common in pediatric populations, exceptwith inhaled Iloprost [51, 52].Endothelin antagonists have shown good results in pulmonary hypertension treatment,especially Bosentan, and now represent a good option with dose standardization in children.Based on experience, it is recommended to start with sildenafil, and then evaluate clinicalresponse. If there is no satisfactory response after up to three months of treatment, acombination of Bosentan Sildenafil is initiated as treatment [53-55].There is extensive experience with sildenafil for pulmonary hypertension in children,although since 2012, the FDA does not recommend its use in patients below 17 years of agedue to the risk of death at high doses [56, 57]. In Europe, conversely, it is approved for use inchildren. At a dose of 1 mg/kg every six hours, several studies have demonstrated satisfactoryresults with sildenafil, and with only few complications reported. Hypotension was theadverse effect most commonly presented in patients. Sildenafil has been used in differenttypes of pulmonary hypertension, and the entire spectrum in age presentation in children,including neonates, for the treatment of persistent pulmonary hypertension in newborns with

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excellent results and safety without long term complications as have been reported by otherauthors [58-61].

Surgical TreatmentAs stated earlier, patients with pulmonary vascular resistance less than 4 Wood units canbe taken to surgery to correct this defect and patients with increased pulmonary resistance > 8units are inoperable. The doubt and difficulty lies in defining the surgical procedure in aborderline patient. Valved patches have been used in patients with VSD [62, 63] andtemporarily occluding the ductus during catheterization in order to observe the response andtolerance to the occlusion [64]. If there is more than one defect, for example the presence of aVSD and ductus arteriosus, one possibility that exists is to close the ductus and leave the VSDopen to see the patients evolution and afterward consider its closure.In "borderline" patients, the inoperable status of the patient must be well established,before definitively rejecting the option of surgery. One example of this is that of a six-yearold girl living at altitude, diagnosed with VSD and severe pulmonary hypertension, andconsidered nonsurgical after catheterization. She underwent a prolonged hyperoxia test thatwas positive (see below), so medical treatment with sildenafil began while living at lowaltitude. Six months later, the patient was catheterized in the same catheterization laboratory;the pulmonary resistance was decreased, permitting the closure of the VSD, and after sixyears of follow up, the patient is asymptomatic. It must be considered that if a patient withsevere pulmonary hypertension and advanced pulmonary vascular disease is taken to surgery,the prognosis is worse than the prognosis of patients with Eisenmenger syndrome and theaverage lifespan is shorter, similar to patients with idiopathic pulmonary hypertension[65,66].In patients with severe irreversible pulmonary disease (Eisenmenger syndrome), lungtransplantation is a last option for the correction of the defect, or a cardiopulmonarytransplantation with acceptable results [67-69]; the drawback is the difficulty in procuringdonors.It is important to keep in mind that in patients with significant pulmonary hypertensionundergoing surgery there are three types of patients: a group of patients in which onceoperated, pulmonary pressures progressively decrease and normalize; another group ofpatients in whom there are no drops in pulmonary pressure; and a third group of patients inwhich the pulmonary arterial pressure and pulmonary vascular disease continues to progressafter the surgery. This last group of patients is similar to patients with idiopathic pulmonaryhypertension and therefore the prognosis is worse than those with Eisenmenger [66]syndrome.In cases with severe pulmonary vascular disease, there are experimental publicationsdocumenting decreased pulmonary vascular disease after performing pulmonary arterybanding [70].

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Pulmonary Hypertension Associated with

Congenital Heart Defects at Altitude. Physiologyand physiopathology at AltitudeIt is important to note some physiological aspects that occur when the altitude above sealevel increases, which are essential to understanding the behavior of the inhabitants of highaltitude. Barometric pressure is the pressure exerted by a column of air over any elementlocated on the earth's surface. This pressure is 760 mm Hg at sea level and decreases asaltitude rises. This is related to the decreasing of the pressure of alveolar oxygen (PAO2), andpressure of arterial oxygen (PaO2). The oxygen saturation and the partial pressure of oxygen(PO2) also decrease as altitude increase [4]. The oxygen concentration is the same at differentaltitudes (21%); however, the partial pressure of a gas = barometric pressure, multiplied by itsconcentration, but barometric pressure is inversely proportional to altitude. So, as the altituderises, the partial pressure of the gas diminishes. The partial pressure of oxygen (PO2) =barometric pressure, multiplied by the concentration of O2:At sea level PO2 is 760 X 0.21 = 159.6 mm HgBogota (2.640 mAsl) PO2 is 560 X 0.21 = 117 mm HgLa Paz (3.600 mAsl) PO2 is 490 X 0.21 = 102 mm HgHypobaric hypoxia refers to the diminished oxygen availability to saturate blood asaltitude rises, which in turn markedly influences the hemodynamic parameters of patientsliving in altitude and alters the characteristics of the pulmonary vascular bed, thereforeinfluencing pulmonary hypertension. For these reasons, the inhabitants of altitudes should notbe approached in the same manner as an inhabitant at sea level.According to the studies by Dante Pealoza, the effects of altitude are noticeably above2,500 meters above sea level, following a parabolic curve of rapid ascent [71] (Figure 5).

Figure 5. Graph showing the effect of altitude due to hypobaric hypoxia. The effect is significant above2.500 meters above sea level, following a parabolic curve (with permission from Professor DantePealoza).

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Classification of AltitudeFor the study of the patient living in altitude and the effects of hypobaric hypoxia,altitude has been classified into several levels. The following classification is used and seemsmost appropriate:Low altitude: Up to 1,500 meters above sea level (masl)Moderate altitude: 1,500 to 3,000 maslHigh altitude: 3000 to 5000 maslExtreme altitude: 5000 to 8000 maslBy the above analysis, it can clearly be seen that altitude is a very important factor in thestudy of patients with PH due to all the implications of hypobaric hypoxia related to theprogressive decrease of barometric pressure and partial pressure of oxygen as altitudeincreases [71,72].Usually in patients with PH, regardless of altitude, the recommendations of studiesconducted at sea level are followed, including the same values of normality regardingpressure and saturation used at sea level, labeling patients who have normal pulmonarypressure as mild pulmonary hypertensive patients and recommending oxygen in newbornsoften without need is a mistake.The decrease in barometric pressure with altitude is related with vasoconstriction of thepulmonary vascular bed secondary to the hypoxia and this is an adaptive mechanism for thosewho live at altitude. However, this vasoconstriction causes increased pressure and pulmonaryvascular resistance, increased cardiac output by increasing the heart rate and may haveincreased stroke volume to maintain proper release of O2. This sustained vasoconstrictionmay eventually cause pulmonary vascular disease [73].The altitude affects both normal patients and patients with different types of PH andtherefore patients with congenital heart defects (CHD). In these last patients, the behavior inaltitude is different from the behavior at sea level, accelerating PH and pulmonary vasculardisease, indicating that at moderate and high altitude CHD must be treated early.In children, and in general in the inhabitants of high altitudes, hyper-reactivity of thepulmonary vascular bed is an important factor and is more noticeable among youngerchildren [72-74]. This factor must be taken into account in the evaluation of children withpulmonary hypertension associated with congenital heart defects in altitude because it mustbe differentiated whether pulmonary vascular resistance is elevated by pulmonary vasculardisease or by vasoconstriction of the pulmonary vascular bed.The above factors must be taken into account from the neonatal period and perhaps fromthe prenatal stage. It is well known that according to studies of the Peruvian group led byDante Pealoza [75,76], pulmonary resistance in postnatal life decreases more slowly than atsea level; it is also known that in some infants with left to right shunts, pulmonary vascularresistance cannot fall back to normal in postnatal life. For these reasons, there is a tendency toacquire early vascular disease in these infants compared to people at sea level. This is the caseseen in Figure 6, showing advanced pulmonary vascular disease in a 6-month-old infant withlarge VSD. This is why these patients should have surgery very early.

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Figure 6. Histological section of a pulmonary arteriole with hematoxylin-eosin staining of a six-monthold infant with large VSD and severe pulmonary vascular disease. Note that there is a light obstructionwith recanalization (grade III of Head and Edwards disease classification). (Courtesy of Susana MurciaMD.)

Taking into account hypobaric hypoxia, and that oxygen is very important part in theevaluation of pulmonary vascular bed in the inhabitants of high altitudes, a test has beendesigned that we named the prolonged hyperoxia test (forthcoming), defined as hyperoxia >80% oxygen for at least 1 hour and up to 24 hours, performing a baseline echocardiogram andtaking a blood sample for BNP prior to the test, and performing another echocardiographyafter hyperoxia as well as the BNP. With this test we were able to rescue patients defined bycatheterization as inoperable or having a poor prognosis, and some have been able to receivesurgery or have evolved satisfactorily.Based on the foregoing, a question arises: In the hemodynamic assessment of pulmonaryhypertension in children at altitude, including the child with congenital heart defectsassociated with pulmonary hypertension, and more specifically in relation to a reactivity testduring catheterization, should the same parameters as at sea level be followed or should moreimportance be given to oxygen levels and therefore to the hyperoxia test? Based onexperience, soon to be published, in altitude the parameters to evaluate the reactivity of thepulmonary vascular bed should be reconsidered, including whether the child is an inhabitantof high altitude with congenital heart defects associated with pulmonary hypertension. This isan important research topic and there is still much to learn.

Eisenmenger SyndromeWhat is now called Eisenmenger syndrome was first described by Eisenmenger in 1897in a 32-year-old cyanotic patient who at autopsy was found to have a ventricular septal defectand, histologically, a severe pulmonary vascular disease. These findings were initially calledthe Eisenmenger complex [12]. In 1958 Paul Wood found eleven pathologies with a similarpresentation to that described by Eisenmenger and coined the term Eisenmenger syndrome

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[13,77], a term that has persisted since then and is defined as the pathophysiologicalpresentation in which a left to right shunt causes progressive pulmonary vascular damagewith increased pulmonary pressures that reach systemic or suprasystemic levels and elevatepulmonary vascular resistance, so that the shunt is reversed, becoming right-to-left orbidirectional shunts, explaining the appearance of cyanosis. In this stage of the disease, anirreversible pulmonary vascular disease has been established with changes greater than grade3 or more of the Head and Edwards classification [14]. As stated earlier, this state can beavoided if left to right shunts are detected and surgery is early. Eisenmenger syndrome occursearlier and more frequently in the post tricuspid shunts (VSD, PDA and aortopulmonarywindow) which occurs in up to 50% of large defects, unlike in pretricupid shunts (ASD) inwhich ES appears later in about 10% of cases [78]. Logically, in the outcome, other factorsare influential, such as the size of the defect, genetic factors and the altitude above sea levelwhere the patient lives.

Clinical PresentationPatients begin to experience fatigue with exercise, chest pain, and cyanosis can betransient or with exercise, which eventually becomes permanent. With time, the cyanosis issevere with clubbing and conjunctival injection. Initially, a significant number of patientspresent with syncope. In the clinical examination important hyperactivity of the RV is foundand closure of the pulmonary valve is palpable. Upon auscultation there is a significantincrease in the intensity of the pulmonary component of the 2nd sound, and an early systolicclick is frequently found. The features of the original defect are lost and a small ejectionmurmur may be found at the upper third of the left sternal border along with a diastolicdecrescendo murmur at the same site (Graham Steel murmur) [17]. These signs are indicatorsthat the patient has an irreversible pulmonary vascular disease and should not be sent tosurgery.

TreatmentIn these patients, the objective is to prolong life and improve the quality of life. Althoughit is important to note that they live longer than patients with idiopathic pulmonaryhypertension; they may live up to 40 or 50 years of age and beyond [78].To improve quality of life, the current approach of the previously mentionedpharmacological treatment includes combination therapy. Prostacyclin + Bosentan orsildenafil + Bosentan, is used, indicating that the BREATH 5 study has shown improvementin patients with the use of Bosentan as shown in randomized studies [79]. Lately, combinedmedical and surgical treatments have been encouraged [51-64,80]. If there is right ventricularfailure, ACE inhibitors and digoxin can be used but care must be taken with diuretics becausethey increase polycythemia, which is characteristic in these patients and may promotethrombosis. It is convenient to use antiplatelet medicine but anticoagulation is controversial.If arrhythmias are present, antiarrhythmic medicines are necessary [80, 83]. For the patientsthat live in high altitudes, it is recommended that they live at a lower altitude above sea level.

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As complications of these patients may include thrombosis, bleeding, epistaxis, brain

abscesses and arrhythmias. In patients with Eisenmenger syndrome it is important to note thatpregnancy is contraindicated because of the high risk of death not only for the mother (about50%) but also to the fetus (about 40%) [81,82]. A last therapeutic option for patients with ESis lung transplantation with correction of the defect or cardiopulmonary transplantation[67-69].

The Adult with Congenital Heart Defects

and Pulmonary HypertensionThis group of patients represents 5-10% of patients with congenital heart defects andincreases progressively as the development of pediatric cardiology expands [80-83]. They canbe separated into three subgroups of patients: a) patients developing Eisenmenger syndrome(this subgroup should disappear, at least in the cases of simple left to right shunts if they hadsurgery in a timely manner), mainly in developing countries where there is not an adequatetreatment of these pathologies; b) patients with complex congenital heart defects where it wasimpossible to perform an ideal surgery and finally develop pulmonary vascular disease (forexample, patients with pulmonary atresia with VSD and significant collaterals); c) patientsdeveloping severe pulmonary hypertension after adequate surgical treatment of the defect.In the pathophysiology of pulmonary hypertension in these patients, in addition to thosefactors previously mentioned in the Eisenmenger syndrome, it is necessary to include factorsrelated with chronicity such as polycythemia, coagulation disorders, and intrapulmonarythrombosis, which is found in 30% of patients with Eisenmenger syndrome.The clinical findings of these patients are basically similar to those found in patients withES, but modified by the findings of the congenital heart defect, dyspnea and syncope beingrelatively common.For diagnosis, the parameters previously indicated for ES are followed, emphasizing theexercise stress test and the 6-minute walk test that helps indicate hemodynamic status, andpatient outcome with treatment [83,84]. Also, it is important to study coagulation disordersand consider polyglobulia. In these cases, erythropheresis was often performed but this shouldbe done only if the hematocrit is over 65% and in these cases it is necessary to replacevolume, emphasizing that these patients should avoid any risk of dehydration. This meansthat from the hematologic point of view, these patients require special handling [85]. It shouldalso be remembered that pregnancy carries a high mortality, so in these patients pregnancyshould be avoided [81, 82].This group of patients has benefited greatly from the current treatment of pulmonaryhypertension with prostacyclin analogs, endothelin inhibitors and sildenafil. With these newtherapies, it has been possible to not only improve the quality of life but to also prolong it.An important group of patients that must be taken into account are patients undergoingcavopulmonary bypass (Fontan), in which case any increase in pulmonary vascular pressurecauses hemodynamic repercussion with heart failure and disorders such as protein-losingenteropathy [83, 84].

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B) Cyanotic Congenital Heart Defects with Increased Pulmonary Blood

FlowThe prototypes of this group are transposition of the great arteries (TGA) and thecommon arterial trunk. In patients with TGA, it should be investigated whether there is anintact ventricular septum (IVS) or if it is a TGA with VSD and/or large ductus. In TGA withIVS, pulmonary vascular disease is found between 6 and 40% at the end of the first year oflife [86,87].In TGA with VSD and/or large ductus, irreversible vascular disease is frequent before thefirst year of life, and this applies to cases of truncus arteriosus as well.In the 70s, several studies on early pulmonary vascular disease associated with TGA inpatients without surgery were carried out, as is documented in the classic study of Neufeld[86].Hypoxia plays an important role in the origin of vascular disease in these patients since itis a potent vasoconstrictor [73]. Moreover, there is a group of patients with TGA andsignificant pulmonary hypertension in the neonatal period, which can be considered apersistent pulmonary hypertension of the newborn associated with TGA. This associationexplains why some patients with TGA with intact ventricular septum do not improve withatrioseptostomy. These patients have been called bad mixers" [88]. With regard topulmonary vascular disease in patients not treated surgically; it is fortunately not the currentsituation because of the tendency of early correction of these patients. It is important to notethat some patients, who experienced timely surgery, may still develop pulmonaryhypertension later [89-91].As in TGA, patients with truncus arteriosus have two factors that contribute to the originof early pulmonary hypertension: hypoxia that leads to vasoconstriction of the pulmonaryvascular bed and increased pulmonary blood flow [92]; for this reason, these patients shouldbe corrected early in the first days of life.

C) Heart Defects That Cause Increased Pulmonary Capillary Wedge

PressureThis group includes all heart defects that cause obstruction to pulmonary venous drainagedirectly by obstruction of the pulmonary veins, or retrogradely by obstruction at the cardiaclevel or the aorta such as cor triatriatum, congenital mitral stenosis, etc. These pathologiesgive origin to retrograde pulmonary hypertension, although the main manifestation is heartfailure and pulmonary edema [17].An essential aspect about this group is that once the defect is corrected, pulmonaryhypertension regresses very quickly. This group also includes the obstructed of totalanomalous pulmonary venous return which causes severe pulmonary hypertension and earlyheart failure in the neonatal period. These patients require early surgical correction.

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D) Heart Defects with Pulmonary Circulation of Systemic Origin or

Malformation of the Pulmonary Vascular BedIn this group, the pulmonary vascular bed receives systemic pressure flow, which causesPH, and may be severe very early on. This group includes the pulmonary artery originatingfrom the aorta and Scimitar syndrome, which is associated with hypoplasia of the right lung[93-95].

E) Complex Congenital Heart Defects

In this group the PH may be secondary to increased pulmonary blood flow, obstruction tosystemic or pulmonary venous drainage, etc. This category unites an important medley,although fortunately the defects of this group are not very frequent.Worth mentioning is the PH secondary to a total atrioventricular septal defect (total AVcanal) which causes early severe pulmonary hypertension, especially if associated with Downsyndrome. These patients should have surgery before 6 months of age.

AcknowledgmentThank you to Dr. Carlos E. Diaz for the collaboration in preparation of the chapter.

NISA Hospital-Pardo de Aravaca. Madrid-Spain

AbstractThe term functionally univentricular heart embraces heterogeneous categories ofcomplex cardiac malformations that, in the context of congenital heart diseases,exemplify one of the most challenging objectives of the study. The management ofpatients with an anatomical or functional single ventricle represents an unlimited taskin the pediatric cardiology and surgical field. The vision of this matter in this undonechapter can be summarized in three stages: the prelude, the epic and the future. In theearly 1940s, the preface era, an experimental work inspired what is named nowadays asthe Fontan/Kreutzer operation the total right ventricular bypass was first reported inhumans in the early 1970s. In the following 40 years several modifications andrefinements of the initial surgical design, improved perioperative care and managementof algorithms-based protocols produced a drastic increase in perioperative survivors theheroic epic. However, when patients grew into adulthood, coping with a completeuniventricular circulation as a result of the palliative procedures, they faced numerouscomplications and multi-organ system difficulties that seriously limited their quality oflife. Continuous research and multidisciplinary efforts in several directions are needed toanswer the future of Fontan failure patients. Perhaps this would include the expectedpotential clinical application of a mechanical new neo subpulmonary ventriclecompatible with a normal life span similar to people with a normal biventricularcirculation.

Corresponding author: Email: mario.cazzaniga@gmail.com.

E-mail: renatarevelchion@yahoo.com.

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IntroductionThe functionally univentricular heart (UH) is a denomination that encompasses aheterogeneous group of congenital cardiac malformations which, with or without unbalancedventricular chambers on its myocardial ventricular mass, makes conventional surgicalbiventricular correction impossible or highly improbable due to their anatomical/functionalcharacteristics or even due to the complex surgical approach [1-5]. The most used therapeuticalternative for patients that fulfil this premise is to create a univentricular hemodynamicmodel in which at least one dominant ventricular chamber is able to take in series, both thesystemic and the pulmonary circulation without any interposition of a subpulmonary pump(Fontan operation) [6]. This strategy is how hearts are currently addressed when a truehypoplasia of one or another ventricle is seen (in univentricular or biventricularatrioventricular arrangement) or perhaps due to the absence or obliteration of ventricularcomponents of its functional anatomical tripartite unit: in any case, the underdeveloped smallchamber is not capable of coping with any circulatory system. In a similar manner, somemalformed hearts with two well-balanced and completely formed ventricular chambers comeup with combined intracardiac lesions that do not allow a surgical approach to restore theoptimal biventricular circulation [4,7,8]. As a result of that, the wide morphologicalexpression of structural defects that are not amenable to a 2-ventricle surgical correction canbe grouped into the more corrected denomination of functionally UH (Table 1); with nodoubt, the management of patients with these anomalies is still an endless challenge in theworld of congenital heart diseases (CHD). Seeing the problem in perspective as a whole, threesections can be discerned as involved in its evolution: the prelude, the epic and thefuture.Table 1. Heart Malformations with Single Ventricle Physiology:Functionally Univentricular Heart

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The prelude has been built with the efforts of pathologists and clinicians committed to anaccurate understanding of the anatomical-clinical substrate; at the same time, active surgicalgroups have explored, in animal experimentation, the feasibility of a partial or complete rightventricle (RV) bypass using innovative techniques. The epic undoubtedly started from theclinical success of the Fontan procedure described in 1971 and was originally designed tocorrect the tricuspid atresia, a real adventure that come by to the present day with constantprogress in all acting fields such as: variations in the original surgical technique, use ofseveral strategies and renewed therapeutic algorithms, sophisticated -pre, intra andpostoperative- care and appropriate clinical follow-up, all that condensed in theuniventricular route. Finally, the future, an exciting stage to be seen in the next decades andthat should include several aspects: implementation in the healthcare system ofmultidisciplinary units specialized in patients that walk into adulthood with fragilehemodynamic conditions that involve clinical difficulties as time goes by; development ofinnovative projects that consider new strategies of management and/or redesign of currentsurgical techniques; and the potential clinical application of subpulmonary circulatoryassistance with miniaturized devices. Currently, most of the physicians who care aboutadolescents and adults with Fontan procedure or its modified types have understood that theresulting UH circulation involved in these palliatives surgeries cannot be compared with thebiventricular model of the normal population and subsequently a shorter lifespan is expected.

The PreludeIn search of a useful nomenclature of the functionally univentricular heartThe process of nomenclature and classification of the malformations in CHD is a desirethat in the last decades has caught the attention of the pathologist, embryologist, cardiologistsand surgeons, all of them expert authorities in the matter [9-13]. The efforts to optimize theknowledge and, at the same time, to improve the management of patients with functionaluniventricular structural anomalies, boost them into a common objective: to formulate aprecise method of diagnostic analysis designed with simple rules, objectives and organizedwith no theoretical or abstract speculations. Not without extended debates, conceptual andsemantic, this intent was condensed in two consecutive steps: 1) a lengthy phase ofmorphologic description of the univentricular universe with embryological support andcorrelation, organized-unified terms and entities, addition of image tools (specificallyechocardiography and cardiac magnetic resonance) that are trustworthy to identifyconnections, morphology and alignment of the different cardiac segments such as ananatomist would do it; and 2) the anatomical-functional surgical phase that begins with therevolutionary breakthrough of the Fontan procedure that acts as an unexpected refereereorganizing the UH playing field to include other cardiac malformations not initiallyclassified as single ventricle, anticipating in an unquestionable way, that they cannot have as atarget the biventricular surgical repair to two ventricles. This background stands for what iscurrently called segmental and sequential morphologic analysis of the heart and vessels (stillwith problems to be solved, mainly in the aspects of heterotaxy syndrome), which consist of amethodical model that, not being the only one possible (other experts make use of differentroads to Rome), evolves in acceptance with accentuated consensus as a method for a precise

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diagnosis, if not all, for the majority of congenital cardiac malformations [14-17]. TheInternational Pediatric and Congenital Cardiac Code (IPCCC) (www.ipccc.net) and the threespecialized Study Committees: Nomenclature Working Group (NWG), Definitions WorkingGroup (DWG) and Congenital Heart Archiving Research Team (CHART) [classifies imagesand videos] that bring together international experts and integrates in combination withother methods the specified model in the encoding process platform and cross-mappingsystem that is also part of the Congenital Heart Surgery Database [18,19].Brief historical review on cardiac morphologyFrom references listed in historical reviews [20-22] it can be assumed that in the XIXcentury two unique malformed hearts were reported; at the end they came out to be the firstparadigms of the UH: double inlet left ventricle (A. Holmes, Canada) and tricuspid atresia (F.Kreysig, Germany) respectively. With evident differences in relation to what we nowunderstand as the atrioventricular connection approach, both lesions shared, among otheraspects, two chambers connected in the ventricular mass: a large, dominant chamber and asmall, rudimentary one. This starting point attracted the attention of pathologists engaged indefining these structural abnormalities that received in the past different and, in some cases,confusing designations: cor triloculare biatriatrium, single ventricle, univentricularheart, single ventricle with outlet chamber, single ventricle with infundibular outletchamber, primitive ventricle, common ventricle, solitary ventricle [8,9,23-27].Participants of avant-garde schools in the field of CHD opened a debate decades ago. It ishistorical now but no less important to solve controversies and classify these uniqueanomalies: R. Van Praagh in USA, M.V. de la Cruz in Mexico and R. Anderson in Europe,among other innovators and qualified experts [9,28,29]. This wide-ranging work developed inthe theoretical, semantic and informative fields and their influence in the pediatric cardiologyand pediatric cardiovascular surgery communities must be acknowledged as it represents thekeystone of our current knowledge. Van Praagh [30] taking into account, as criteria, theabsence of ventricular sinus (inflow tract) and ventricular septum (partial or total) proposedthe first classification of the single or common ventricle defining 4 types:A)B)C)D)

single left ventricle (absence of right ventricle sinus)

single right ventricle (absence of left ventricular sinus)common ventricle (rudimentary interventricular septum)undetermined ventricle (absence of inflow tract and interventricular septum)

This analysis was based on specimen collection that, intentionally, did not included caseswith mitral or tricuspid atresia. The author pointed out the nature of the classical singleventricle with rudimentary outlet chamber that was revealed to be mainly a dominant leftventricle and a right ventricle infundibulum (type A). In addition, he also defined subtypesbased on atrial situs and the relationship among the great arteries; in essence, this descriptivescheme anticipated the morphological segmental model of analysis. Later, the same authorand other experts in the field, highlighted the connection among atriums and the principalventricle in these ventricular anomalies can hold two patent atrioventricular valves (doubleinlet ventricle) or a common atrioventricular valve (common inlet). Finally, and acceptingthat the single ventricle usually presents two chambers related in the ventricular myocardialmass (the presence of a solitary ventricle is exceptional) means that the dominant ventricular

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phenotype is recognizable by the morphologic pattern of the apical trabecular component, so

it is possible to identify three patterns that, in order of frequency, are left ventricle (LV) type,right ventricle (RV) type and undetermined type (the older type C was re-classified as a largeinterventricular defect). However, the use of embryologic terms as sinus, conus, outletchamber, infundibular outlet chamber, foramen bulboventricular (septal defect whichcommunicates both ventricular cavities), as well as the non-inclusion of tricuspid and mitralatresia in the first classification, raised many controversies [2,24,26,30,31].R. Anderson and cols. [1,7,10,32-34] integrated many scattered criteria and rearrangedterms interpreting them in numerous papers with two essential principles that were probablyat the base of the debate: 1) the key of the diagnosis of the single ventricle is theuniventricular type of the atrioventricular (AV) junction (the entire AV junction connectswith one ventricle), and in this set two ways of connection are possible: double inlet ventricle[DIV] (two atrium connected with the dominant ventricle) or the absence of one AVconnection (one atrium, right or left, does not connect with any ventricular chamber) and insuch a way the classic tricuspid (TA) and mitral atresia are, in fact, included in this principle;2) the ventricle is documented by its anatomical and functional tripartite nature: inlet(identified from the AV junction to the distal insertion of the valve tensor apparatus), apicaltrabecular portion (typical of trabeculated pattern) and outlet (supports the semilunar valves).The same group of experts, immersed in an intense debate, supported the concept thatwith this principle in mind, the so called outlet infundibular chamber presented in thedouble inlet LV is, actually, an incomplete RV (absence of inlet), rudimentary(underdeveloped), which apical trabecular portion is separated from its homonymous of thedominant LV by an interventricular septum well recognizable by the distribution of theconductive tissue and the perforate branches of the coronary vessels. They also point out thatthe intrinsic morphological characteristics of the rudimentary RV are similar in both types ofuniventricular AV connections: double-inlet ventricle and absent right sided AV connection(classic TA). With morphological and topographic description, Van Praagh and de la Cruz[15,35) proposed the first classification for complex heart malformations and Anderson andthe European group [13,14] developed and extended the sequential-segmental analysis thatnot only integrates all the data but focuses attention onto the implication of recognizing, amidother aspects, the nature of the inter-segmental connection of the 3 segments or cardiac blocks[atrial chambers, ventricular mass and great vessels] with systematic rules to obtain the mostcomplete and adjusted diagnosis. The method of morphologic sequential and segmentalanalysis includes the following steps:

Definition of the atrial arrangement

Type of atrioventricular connectionMorphology of the atrioventricular valvesVentricular morphology, size, topology and inter-chamber relationshipInfundibular morphologyGreat arteries relationshipPosition of the heart in the chest with base-apex orientationAbdominal-thoracic arrangement (visceral situs)Associated cardiovascular malformationsNon-cardiac anomalies syndrome or genetic context will be analysed

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The sequence to obtain this systematic information is variable according to the

observational method employed, the clinicians expertise and the available diagnostic tools.Echocardiography would be the initial diagnostic approach [36] but magnetic resonanceimage (MRI) will overcome many of the limitations for the extra cardiac features. Bothtechniques will be the non-invasive diagnostic images for a complete view of the cardiac andextra-cardiac components. To develop the sequential and systemic methodology is essential torecognize the diverse and persistent anatomical elements that belong to each segment of theheart or cardiac block and, what is more important, to keep in mind that these explicitconstant morphological references are present in normal hearts as well as in malformed ones;these are:1. Morphology of the atrial appendage to be able to recognize each atrium [right:triangular, broad base, ploughed by pectinate muscles extended up to the orifice ofthe coronary sinus; left: narrow opening, hook shaped and spare pectinate forms]2. Pattern of the apical trabeculated portion to identify ventricular chambers [LV: thintrabecular arrangement; RV: thick bands configuration]3. Define the origin of the coronary arteries and the superior distribution of the arterialtree [aorta: arterial branches run toward the superior half of the body and, at least, thepresence of one coronary ostium at the Valvalsa sinus level; pulmonary artery: theremaining vessel that does not accomplish the previous description]Epidemiological dataEpidemiological studies, either previous or most recent, point out that the incidence ofCHD is located in a range between 4-10% of live newborns. TA and DILV are represented in0.05-0.08% of live newborns, and between 1.3-2.7% of the entire CHD. DILV is prevalent(70%) with respect to DIRV (< 20%); the type of undetermined ventricular morphology isuncommon (<10-15%) and often is part of the heterotaxy syndrome. In the DILV theventricular-arterial discordance (L-transposition) prevails, hardly present with normallyrelated great vessels (Holmes heart); the double outlet or malposition of the great vessels ismore frequent in the DIRV and in the undetermined ventricle. In the double inlet ventriclewith right atrioventricular valve atresia (classic TA) the relationship of the great vessels ismainly concordant (70%), in the smaller percentage of the discordant subtype. FromHoffmans study [37] the estimated prevalence of major forms of CHD per 1000 livenewborns can be assumed: single ventricle (SV) 0.83, hypoplasic left heart syndrome (HLHS)0.22, atrioventricular septal defect (AVSD) 0.34, tricuspid atresia (TA) 0.9, double-outlet RV0.12, transposition of the great arteries (TGA) 0.30, many of them categorized as functionalUH.The surgical history of partial / total right heart bypassFor centuries physiologists considered the dual concept of the pulmonary circulation,vital for life: the RV behaves as a subpulmonary pump propelling blood through thepulmonary vessels toward the left chambers, a task that contributes with the same purposewith another mechanism, the respiratory cycle with the couple inspiration/expiration. Animalexperiments carried out in the 40s in which the right myocardium was damaged questionedthat argument as it was found that, in the acute period and under certain circumstances, thepulmonary blood flow was kept even with absent or altered RV function [38,39]. Years later

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there was the onset of what was intended as the Fontan procedure [40], a period of severalexperimental attempts with different surgical approaches intended to demonstrate that thetotal or partial exclusion of the RV was possible. As reflected in historical review papers [4042] numerous surgical attempts with various technical details proposed the current operatingscenery that we know nowadays. Hurwitt in 1955, unsuccessfully attempted theatriopulmonary anastomosis (total RV bypass) in a dying child with TA employing theconcept of pump action of the right atrium as an anticipation of the yet to come Fontanprocedure [43]. From all the clinical and experimental attempts, the partial exclusion of theRV by means of the cavopulmonary shunt (end to side superior vena cava to right pulmonaryartery) turned out to be extremely useful and soon its clinical application spread widely topalliate different cyanotic congenital heart diseases. Although the first clinical successes werereported in the 1950s, in an almost simultaneous manner in Italy, Russia and France, it wasW. W. Glenn in USA who confirmed its clinical usefulness in numerous patients and allegedthat around 30-40% of the superior systemic venous flow is distributed in the right pulmonaryfield; this technique became commonly called the classic unidirectional Glenn shunt [44,45].Due to the late morbidity (occurrence of pulmonary arteriovenous malformations) thistechnique was side lined in the 70s. By that time the first clinical attempts with thebidirectional cavopulmonary shunt were reported successfully by the way [46-48] andgradually joined the surgical arsenal of the UH with the name of bidirectional Glenn shunt(BDGS) [the rescue of the Glenns !].

The EPICAnother subject that arouses so much attention in the international biomedicalcommunity and some other connected disciplines is univentricular circulation, a particularcirculatory model in human subjects. We are now getting into the 4th decade for palliativereconstruction in CHD with no amenable biventricular surgical correction, however theodyssey continues [49]. Proof of that is the large amount of quotations provided by severalbiomedical webs [Medline, PubMed, journals and books on line]: more than 3,000 reportscome out when you search for a bibliographic review with the key word Fontan procedure,Fontan operation, Fontan-Kreutzer operation or cavopulmonary anastomosis.No doubt the epic started with the complete bypass of the RV and the early surgicalsuccesses reported by Fontan in 1971 and Kreutzer in 1973 [6,50] with a technique initiallyintended for patients with TA and reduced pulmonary flow: the atriopulmonary anastomosis(APa). The original technique was set up with: 1) classic Glenn anastomosis, 2) APa thatprovided blood flow to the left pulmonary branch and 3) closure of the interatrial defect thatended the right to left mixing blood.Rather soon, different technical details were corrected improving the initial procedure, tomention some: the use of valved grafts positioned at the entry of the inferior vena cava intoright atrium and/or at level of the pulmonary artery anastomosis (position in which also wasbriefly used as the native pulmonary valve) that was later abandoned; the anterioranastomosis prone to have a sternal compression was replaced by a wider posterior with nochance of extrinsic compression and, pretty important, the anastomosis encompassed bothpulmonary artery branches with no need of previous classic Glenn or related procedures

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(another additional native or surgical source of pulmonary flow were abolished); the potentialpump function of the right atrium was taken into consideration [it was well known topathologists that the myocardial wall of the atrium was thicker in TA [51] totalling acombined support of adequate diastolic ventricular function and an optimal mechanism ofpulmonary ventilation that supports the hemodynamic concept of the surgical technique. Allthese aspects together set for the first time a successful survival with a remarkablehemodynamic in human being, commonly known as Fontan circulation or univentricularcirculatory model. With some more advantageous modifications it became popular worldwideand also extended the anatomical substrate to which was intended for other malformationsdifferent to DILV or TA in which the morphological type of the main ventricle was right orundetermined [52-56]. Other old techniques are already considered to be past history [57-59].Almost at the same time the classic Glenn was modified to the present BDGS withbenefit [47,48] being both stated as a versatile complement to the Fontan operation andadjusted upon clinical demand [60-63]. Likewise, the BDGS was used in 1984 (Kawashimaoperation) in patients with heterotaxy syndrome and left isomerism who had absence of theintrahepatic segment of the inferior vena cava with azygos vein system continuation. Thispeculiar anatomy involves the entire systemic venous flow distributed in both lungs by thesuperior vena cava except the hepatic veins that remain connected to the atrium; with theBDGS the patient improves oxygenation but the so called hepatic angiogenesis factoreludes the vascular pulmonary field with the resultant advent of pulmonary arteriovenousmalformations [64].Little more than a decade after the Fontan-Kreutzer operation, other problems must benoted, the occurrence of a severe progressive right atrial enlargement that promotesarrhythmias with a poor intrinsic kinetic energy to lead the systemic venous flow to the lungs.In 1988 Marc de Leval developed and applied, both in animal experiments as well as inclinical trials, the so-called total cavopulmonary connection (TCPC) which, in its originalconcept, involved two concomitant procedures: BDGS and a tubular intra-atrial tunnel with abaffle that goes from the inferior vena cava to the proximal right pulmonary artery (withextended atrial line sutures). This last part of the procedure was named and is expressed in theliterature as a lateral tunnel (LT) [65-69]. This new approach obtained: lower power losses ofthe venous pathway that reach the pulmonary vascular bed without systolic impulse, bettercirculatory efficiency and, over time, less incidence of arrhythmias since only a part of theatrial myocardium would be affected by the high pressure of the venous circuit. In the 1990snew progress appeared: 1) the BDGS became used as an interim before Fontan and itsmodifications (two stage strategy); 2) some groups modified the BDGS that becomes thehemi-Fontan with an easier surgical approach and with anticipation of eventual Fontancompletion with a LT, and 3) the implant of a prosthetic extra cardiac conduit (ECC in theliterature) that leads the flow on the outside of the heart from the inferior vena cava to thepulmonary artery (it does not require difficult atrial sutures, so a lower incidence ofarrhythmias is expected) [70-75] (Figure 1). An important improvement, no less important,was the baffle fenestration of the LT (easy to do) or in the ECC (more complicated toperform) deliberately created by the surgeon (it was applied to children with possiblyreversible or treatable risk factors). Rapidly, its indication was enlarged for patients with preFontan standard-risks). It is a single communication at the level of the LT or the ECC with thepulmonary venous atrium that allows a right to left shunt, which guarantees a consistentcontribution to the cardiac output for better circulatory adaptation in the immediate

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postoperative: low mortality, significantly less pleural effusion and significantly shorterhospitalization even if it induces a mild degree of cyanosis [76-78].The feasibility of performing such techniques without extracorporeal circulation, or withminimal circulatory support was successfully explored [79]. William Norwood took a big stepforward with the procedure that bears his name on the way to palliate neonates with HLHSand gave an impulse toward other recommendations: the algorithms of the two-stagedprocedure, as a sequence of planned actions not due to clinical requirements, performed at ayoung age to reach the complete Fontan; this strategy attempted to reach a more effective andearly unloading of the systemic ventricle that positively impacted morbidity and mortality[80-83]. Other advances in the perioperative field clinical management, anesthesia orintraoperative procedures are already well established in the everyday routine. One of thethem, the modified ultrafiltration after weaning off cardiopulmonary bypass, significantlyreduced the systemic inflammatory response (suppression of cytokines and harmful factorsfor the myocardial function and the pulmonary vascular resistance) confirmed as independentvariables associated with a decreased incidence and duration of the pleural effusions,improved pulmonary and ventricular function and decreased postoperative bleeding followingFontan [assured a more comfortable immediate postoperative period] [84,85].In some selected patients (for example in a small RV or Ebstein malformation), palliativesurgery can be used, named the one and one half ventricle repair (BDGS plus closure of theinteratrial communication) dividing the two circuits, pulmonary and systemic, keeping intactthe normal connection of the inferior vena cava with the right sided heart and their normalFIGURE artery1.- atThetypesof Fontan procedure -MRIpulmonarythe threesame time[86,87].atriopulmonaryanastomosis

total cavopulmonary connection

Right pulmonaryartery

BDGS

LeftPulmonaryartery

leftatrium

dilatedright atrium

lateral tunnel

extracardiac conduit

Figure 1. The three types of Fontan procedure MRI.

Single ventricle physiology

Since the fetal stage and already in the postnatal period, patients with a single ventriclepresent a model of circulation in parallel: a super ventricle ejects simultaneously to thepulmonary and to the systemic arterial system (via ductus or through a native outlet)depending upon the resistance of each circuit. This ventricle is dilated, with some degree of

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hypertrophy in accordance (it is estimated that it works with more than 200% of the expectedvolume with respect to a normal LV in biventricular fashion); both conditions are moreobvious when a consequence of the normal decrease of pulmonary vascular resistance isblood flow increase, through an unobstructed outflow tract, after palliation by anaortopulmonary shunt or untightened pulmonary band. In the past, this period of parallelcirculation protracted in time with a detrimental impact on ventricle and pulmonary vascularbed. Immediately after single non-staged Fontan there is a sudden reduction of ventricularsize (< 50-70% of the normal value indexed with the body surface area) with myocardialmass prevalence (mismatch mass/size and abnormal diastolic function) that affects thepostoperative progress [88]. The BDGS as 1st stage lessens this mechanism so that itcontributes to a slow-paced unloading without an uneven overgrowth. Some authors avoidany simultaneous pulsatile additional flow (more cyanosis, effective ventricular unloading),others prefer to maintain an additional source of pulsatile flow appropriately regulated ("alittle additional flow") to induce the normal development of arteries and distal pulmonary bedwithout a disproportionate increase of the ventricular preload, at the same time there is lesshypoxemia. Gewillig points out: not too much for the ventricle, not too little for the lungs[89]. This difficult balance is not always easy to obtain in practice but it is essential for thepatient. When the Fontan circulation is completed as 2nd stage, the single ventricle preloaddepends almost exclusively (the so called suction effect has not been fully understood) of thepulmonary vascular resistance (transpulmonary flow/gradient). Without doubt, it is theintrinsic condition of the total univentricular model in series in a way that the single ventriclesuffers a chronic preload deprivation with little or poor functional reserve on exercise (there isno prepulmonar systolic impulse). All that, contrary to what happens in normal subjects,explains the chronic low output more evident on effort that is not sufficientlycompensated, neither with the afterload nor with the contractility, only with a modest increaseof the heart rate. The chronotropic auto regulation theory in the univentricular circulation isinteresting: a very high heart rate on effort (usually the rule in normal people) would reducein excess the diastolic time with the consequent severe impairment of the cardiac output. Theslow-paced ventricular unloading earlier imposed and the protection of the pulmonaryvascularity has created a reduction of hospital morbi-mortality and at midterm, as well, aneffect of "recruitment of new candidates for Fontan (reduction or disappearance of AV valveinsufficiency, low pulmonary resistances, lessening of the hypertrophy, among others).Redington, Gewillig, and other experts reviewed in detail the univentricular physiology andits palliations [90-95]: the final model subsists with 3 well known conditions: 1) chronic lowsystemic output [in essence regulated by the non-pulsatile resistance of pulmonary vascularbed], 2) chronic increase of the systemic venous pressure [paradox physiology: > venouspressure and < pulmonary pressure] and 3) normalization of hypoxemia (in absence offenestration). A remarkable aspect is, being the arteriolar pulmonary resistance is adeterminant factor for early and late success in univentricular circulation, the hemodynamicdetermination of the pre Fontan operation has less reliable data (different source of flows,stenosis or distortions in the pulmonary arteries, mathematics assumptions, etc.). Alsoobtaining a low transpulmonary gradient preFontan does not guarantee the desired value(between 5-8 mmHg) in the early and late postoperative period. Choussat described in 1978as many as 10 requisites to select the most favorable patients with acceptable conditions forpalliation with the Fontan technique and not following them would become a therapeuticfailure. Since 1986 the criteria have been reviewed or reformulated (for example Fontancirculation can be completed at an earlier age, the pulmonary arteriolar resistance has to be 2 units/m2), some were excluded, some others not reflected before were added (systemic

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different independent variables associated with the immediate mortality were reported(Downs syndrome, geographic altitude, lack of fenestration, among others) [96-100].

Current Phases of the Univentricular Route

Currently, for optimal diagnosis and medical-surgical management of the heterogeneousvarieties of functionally UH, diverse algorithms have emerged, all of them attempting tocomplete the Fontan circulation. To achieve this goal it is necessary to have an adequate levelof development and complexity of the perioperative neonatal and cardiovascular surgeryprogram of the center. A great deal of the current approach in innovative teams is due to theimpulse and relevant impact that was introduced by the Norwood operation. Nevertheless,there are differences in management among institutions, some conceptual, other operative orrelated to the preferences of the surgical team. In any case, several fields of controversy existfor example, in the application of early procedure strategy. Some experts propose the earlyuniventricular route as a scheme of a more updated management in the different phases,medical, interventional and surgical with the expectancy of obtaining a reduction of the earlyand late morbi-mortality, extend the Fontan circulation longevity and decrease the incidenceof complications [27, 101-106].The suggested phases of the univentricular route are (see Table 2):Table 2. Current Management: The Univentricular Route ... phases, stages,strategies .

Phase AFetal diagnosis and management. A fetal diagnosis of a great deal of the anomalies of thefunctionally UH by echocardiography is possible in skillful hands between weeks 18-20 ofgestation paying attention to a 4 chambers view that visualizes the type of the atrioventricularjunction and the presence of one small ventricle. The study is completed with other

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in the first echo scan: 1) the degree of under developed ventricle, 2) characteristic of theforamen ovale and its Doppler flow pattern, 3) relationship of the great arteries and theasymmetry among them (anticipate potential development/progression of systemic orpulmonary obstruction), and 4) extra cardiac associated malformations. However, it is wellknown that anomalies that form the subgroup of the HLHS undergo changes during thepregnancy, in part due to flow disturbances; thats the reason why some prenatal care unitspropose serial tests for any variety of UH for a longitudinal screening of the fetalhemodynamic and verification of progress/changes in the structures. This fetus follow-upstrategy not only adds to the knowledge and interpretation of the mechanisms that influencethe development of heart disease in utero but allows for planning interventions, if applicablein selected cases (pulmonary or aortic valvuloplasty, atrial septostomy), and even anticipatesan approximation of the postnatal prognosis which assists the selection of a specialized centerfor the delivery in agreement with the ongoing programs of neonatal cardiovascular surgery.From reports that analyse the outcome of a fetus with UH, some information has emerged: 1)the detection rate in tertiary perinatal centers is 80-95% and anticipates quite rightly theneonatal therapeutic actions in more than > 60%, 2) 20-25% of the total number of fetuseswith extracardiac malformations or syndromes, 3) the in-utero demise is infrequent < 3-5%,4) termination-abortion after parents-counselling fluctuates between 15-50%, 5) fetal loss forcomplications in intention to-treat or secondary to fetal intervention is observed in < 1020%. No less important are two other aspects that are highlighted in the literature: a) thepostnatal mortality is not affected by in-uterus diagnosis, and b) the positive impact of theprenatal diagnosis is significant for morbidity and patient clinical status in the neonatal period[early application of treatment before the onset of circulatory failure or shock secondary toductus closure]. The prenatal diagnosis of CHD allows the parents to know in detail thecharacteristic and nature of the malformation, the intervention and/or surgical repair neededfor survival, the immediate postnatal prognosis and the long-term therapeutic strategies to beapplied. Simultaneously, the prenatal unit team offers genetic counselling to the couple whoseimportance is remarkable: the risk of having CHD in siblings of patients with HLHS mayreach 35% while in some other categories of UH, the risk for siblings and offspring doesntseem to exceed 5%. In any case, this multidisciplinary management of information and earlycounselling to parents get them ready to face the care of a child with life-threatening CHDwho will require multiple attentions throughout his life and, at the time, gives them theopportunity to reflect on the choice of termination of pregnancy. It should be pointed out that,even with a precise fetal diagnosis, in some varieties and subtypes of the functional UH it isnot possible to anticipate if they will be suitable or not to univentricular palliation [107-115].

Phase BPostnatal period, diagnosis reassessment, treatment strategy, 1st stage palliation, interstage evaluation. The importance and expression of clinical impact in the newborn or neonatewith single ventricle physiology will depend upon well-defined anatomical features:obstruction to the systemic or pulmonary flow, obstruction to the ventricular inflow(obstruction or intact atrial septum in right or left AV valve atresia), systemic or pulmonaryvenous return abnormalities (heterotaxy syndrome) and presence/grade of AV valve

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regurgitation (more frequent in hearts with common AV valve). The basic axes of proceduresand management in this phase depend to a large extent on whether the diagnosis is previouslyknown (prenatal), if de novo is suspected as a consequence of routine application ofneonatal screening strategies during the usual newborn hospital stay or it is recognized weekslater after the appearance of clinical signs and symptoms (mainly cyanosis for insufficientpulmonary blood flow, heart failure due to overload or circulatory collapse/shock when thesystemic circuit is ductus-dependant). The significant neonatal action includes: 1) fast anddetailed confirmation of the anatomical diagnosis (echocardiography is vital in this process, itis especially necessary to appeal to more sophisticated imaging techniques such as MRI) and2) prompt medical management in the Neonatal Intensive Care Unit (NICU) in order to reachthe clinical stability (Prostaglandin E is mandatory to preserve the ductal permeability),optimize the total cardiac output and the systemic oxygen delivery. Once defined and thescenarios described, and according to the anatomical malformation category, four types of 1ststage palliation can be required:1) Total aortic reconstruction: Norwood operation or hybrid process for neonates withHLHS or single ventricle variants with severe aortic obstruction. The reportedhospital survival with this approach fluctuates between 70-93%; 10-15% of neonatesrequire ECMO or cardiopulmonary resuscitation in the post-operative period; at 12months transplant-free survival is around 75%. Currently the primary heart transplantis unusual in patients with HLHS or its variants; only exceptionally will it beindicated as an alternative in the presence of RV dysfunction and/or severe tricuspidAV valve [101,116,117].2) Aortic arch repair in association with unrestricted pulmonary blood flow: coarctationrepair associated with the Damus-Kaye-Stansel (DKS) operation in neonates withevident or potential subaortic obstruction (due to restricted ventricular septal defect).To adapt the pulmonary flow a systemic-pulmonary anastomosis is simultaneouslyperformed through a prosthetic graft (modified Blalock-Taussig shunt-BT). Theassociation between the pulmonary banding and the appearance/progression ofsubaortic stenosis in the setting of DILV or TA with transposed great arteries is wellknown. It is possible to substitute the DKS operation with a pulmonary banding if thetwo requisites are satisfied: the banding is left in place for a short period of time anda scheduled close echocardiographic surveillance (early planning for 2nd stagepalliation in 2-3 months). This last action plan does not permanently rule out theDKS operation, which may be performed concomitantly with the 2nd stage palliationif the subaortic stenosis progresses to an obstructive degree. In some centers thepalliative arterial switch has been proposed as an alternative to sort out the systemicobstruction and with well-selected cases the results are encouraging. The hospitalsurvival with this varied approach of surgical palliation ranges between 85-90%[118-121].3) Excessive pulmonary blood flow: in the absence of subpulmonary stenosis the initialapproach to reduce the pulmonary over circulation is the pulmonary banding.Disadvantages of this simple procedure are: migration of the banding withobstructive consequence in one or both pulmonary branches, uncontrolled flow andpulmonary pressure (little tightening) so it will perpetuate the signs and symptomsof heart failure, or too tight with severe reduction of the pulmonary flow that

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clinically expresses itself by severe cyanosis; any of these symptoms must be solved.With these problems in mind, some groups propose dividing the pulmonary trunkand regulating the pulmonary flow with a BT shunt. With any of these actionshospital mortality fluctuates between 5 and 13% [122,123].4) Insufficient pulmonary blood flow: the modified BT shunt (small graft of 3 or 3,5mm) is the therapeutic choice for increasing/adjusting the inappropriate pulmonaryflow in neonates with atresia or severe pulmonary stenosis. The reported mortalitywith this strategy stands for 5 and 15%, so it is not surprising that interventionalcardiologists perform ductal stenting in neonates to avoid the initial surgicalpalliation and go straight for a BDGS. The postoperative therapy with antithromboticagents is essential as the main cause of graft occlusion is related to thrombosis; insome selected cases it may turn to interventional catheterization (thrombolysis plusstent implant into the shunt) [124,125]

The exception to all this perioperative medical and surgical management in the neonatalage is reduced to a small proportion of patients (<10%) with UH variants because of their"very good balanced circulation: Qp/Qs 0,9-1:2 and arterial oxygen saturation around 8085%.

Phase C2nd stage palliation (the unloading ventricle process). It is intended to perform,between 3-6 months, the cavopulmonary shunt with two technical options depending on thepreference of the surgical group and largely anticipating the next step or path towards thecomplete Fontan: BDGS or HemiFontan (wide side to side superior vena cava-right atriumjunction and right pulmonary branch plus closing the created communication between theatrium and pulmonary artery with a patch). From the hemodynamic viewpoint they areequivalent; the first one is used more frequently, is easier and preferred for surgeons that willcomplete Fontan with an ECC. The second one is more complex, requires working closely tothe sinus node (with potential injury to the tributary vessel or their innervation) and ispreferred by teams that go for LT. The associated anomalies, if it is necessary should becorrected in a concomitant approach (severe AV insufficiency, distortions or stenosis of thepulmonary branches, subaortic stenosis, among others). Some groups prefer to abolish anykind of additional pulsatile pulmonary flow at the moment of the BDGS (less post-operativeincidence of pleural effusion at the expense of more cyanosis) while others prefer to maintainpervious pulsatile flow systemic-pulmonary shunt, pulmonary banding, and nativesubpulmonary stenosis relying on better oxygenation in the postop and a favorable effect onthe pulmonary vascular tree development growth. The immediate postoperative risk factorsare: bilateral Glenn, preoperative mean pulmonary artery pressure >15-17 mmHg, arrhythmiaand ventricular dysfunction. The operative mortality of this phase tends to be < 5% [126,127].Again, it has to be highlighted that around 10% of neonates and infants with functionally UH,due to a good systemic /pulmonary blood flow balance, will not need any previousintervention to the BDGS.

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Phase D3rd stage palliation. Total cavopulmonary anastomosis, the last step to complete theFontan circulation. Around 2-4 years of age the univentricular circulatory model in series iscompleted with the deviation of the infra-diaphragmatic systemic venous return conveyingthe inferior vena cava to the pulmonary artery by two technical options: 1) the LT or 2) theECC. Both techniques have advantages and disadvantages although currently the majority ofthe centers prefer the ECC, even if there is a controversy about it; some surgical groups prefera routine fenestration. The operative mortality of this phase is < 5% [128-132]. It must beconsidered that some patients with acute or subacute failed Fontan completion require earlysurgical management: 1) Fontan takedown to a BDGS and/or arterial shunt in order tostabilize the univentricular circulation or 2) heart transplantation. Almond reported theoutcome of 53 patients in whom a takedown was performed at the time of the Fontanoperation itself (22%), or before a year after Fontan completion (78%), among survivors(29/53, 55%), 65% were submitted to redo-Fontan (> 2 years later), 10% underwent cardiactransplantation and 24% with BDGS as definitive palliation [132]. The Fontan completionperformed by interventional catheterization was reported [133].During the transition between phases B, C and D the child passes a relatively short periodof cyanosis with little clinical significance, therefore they require a close clinical surveillance.In summary, the combination of a prompt operative strategy and strict selection of thecandidate improves the immediate outcome, although it remains to be endorsed whether thisprotocol increases longevity and quality of life of survivors. Cardiac catheterization isnecessary before the BDGS and the modified Fontan completion to define the hemodynamiccondition and add the possibility of performing interventional procedures.

Phase EAdolescents and adults. Late scheduled program of personalized assessment of survivors(specialized Fontan circulation clinic team with interdisciplinary distinctive in a collaborativeworking group that discusses each patient with other subspecialists) to monitor progressionand solve the clinical and hemodynamic problems secondary to low chronic output and theendothelial dysfunction that this condition promotes [protein-losing enteropathy,demineralized bone, somatic growth, neurological disorders, hepatic disease, thromboembolicphenomena, among others]. Also to monitor extra cardiac procedures, pregnancy counseling,antibacterial prophylaxis, social support and other kinds of support the patient requires. [134].

Late Complications Failing Fontan

A substantial variety of complications happen in the mid- and long-term follow-up ofpatients palliated with the Fontan procedure and/or its modifications [135-141]. There isagreement that these are largely time-dependent and many of them secondary to the "intrinsichemodynamic properties" in Fontan circulation. At the same time, the technical modificationsand the different algorithms used for patient management that were, and are, applied over the

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years embraces a set of complications that, at first glance, includes survivors of the initialsurgical techniques. So, in order to have a realistic and truthful scrutiny, we have to wait acouple of decades to validate if the present process of precocity adopted in the currentuniventricular route involves lengthier longevity, less incidence of complications,interventions, redo and/or less late gradual attrition than the one observed in olderpatients. In any case, these remarks do not invalidate active approaches to palliate,ameliorate or anticipate the complications already recognized in the literature or evenunexpected (Figure 2). Furthermore, there is an agreement about the aggressive study of thesepatients and the periodical assessment of the Fontan circuit by means of catheterization orMRI (eventually cardiac CT angiography to specific issues) to anticipate residual lesions orsequels that can be amended with interventional cardiology or surgery before they have aflorid clinical expression [142].Complications have been gathered under the name of failing Fontan [143-147]. Asecond late gradual rising hazard function for death 5-10 years after the APa is well known;the survival estimated curve was predicted to be 70-75% al 15 years of follow-up, amongothers, one of the identified risk factors was older age at operation [98,148-152]. Currentlythe overall late survival predicted and well documented, is around 80-85% at 15-20 yearsfollow up [153-155], yet, there is no evidence whether this rate could be improved with thetechniques and current algorithms in follow up longer than 25-30 years. The actuarialfreedom according to mode of death at 25 years follow-up was: event-free survival related toheart failure 95.6% (increasing hazard risk after 10 years follow-up), related to sudden death96.3% (annual incidence of 0.15%), and related to thromboembolism 91% [151]. Therecognized risk factors associated with late mortality have been summarized in: 1) the type ofventricular morphology (the right seems to induce worst late results in respect to LV typealthough there is a debate about this specific issue), 2) the heterotaxy syndrome (common AVwith significant insufficiency), 3) protein-losing enteropathy, 4) elevated right atrium pressureafter Fontan, 5) arrhythmia, 6) thromboembolism (due to lack of aspirin prescription or anyother anticoagulant therapy) and 7) reoperations (pacemaker, Fontan revision and conversion,heart transplant).Functional capacity, quality of life and some other complications.- When the functionalclass is estimated with the NYHA classification it is remarkable that around 70-80% ofpatients are allocated in class I and II, however over time such percentage seems to declinefor many reasons of sudden, unexpected and insidious onset. This fact emphasizes the needfor a multidisciplinary and programmed screening to study and anticipate, if possible, thedifferent late clinical problems that happen in this particular population during the follow up.Another aspect of interest in this field is the discordance between the perception in theassessment of health reflected by the patient and close relatives and the objectivemeasurements that assess the clinical status. Different reports from the Pediatric HeartNetwork Investigators - Fontan Cross-Sectional Study - National Heart, Lung, and BloodInstitute [www.pediatricheartnetwork.com] suggest that not only is there a functionallimitation in survivors but that, at the time, this affects their quality of life (Child HealthQuestionnaire CHQ and ADH adult model: www.pedsql.org). One of the most investigatedparameters has been the functional exercise performance; in 546 patients Paridon detected, at8 years post Fontan, an average for maximum oxygen consumption of 65% with respect to theexpected normal, this percentage value is less in the older Fontan population in Dillersreport; and finally there is an increased risk of hospitalization [156,157]. Van den Bosch

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reports a reduction of physical functioning; mental health and general health perception in 36adult survivors with an average of 15 years follow up [158]. The evaluation of thecardiopulmonary response to exercise reflect levels of interaction between the reduction ofthe functional capacity and the concomitant ventilatory disorders; the factors associated withthese observations are: inappropriate chronotropic response, atrioventricular asynchrony,ventricular-arterial uncoupling, presence or not of hypoxemia (due to fenestration or nonfiliation right to left shunt), restrictive phenomena of the pulmonary function (for examplethoracic distortion secondary to previous palliation or scoliosis) and increased post pubertalbody mass. In any case, the most important limiting factor of the functional capacity is aninadequate cardiac output to meet the metabolic demands to the maximum effort (inability tomeet the demand of high transpulmonary flow due to limited preload rather than of abnormalsingle ventricle systolic function). A functional score was recently developed couplingventricular ejection fraction (by echo), predicted maximal oxygen consumption (%), childhealth questionnaire and brain natriuretic peptides. Risk factors for poor functional scoreswere found to be: RV morphology, elevated preoperative end diastolic pressure, pre Fontanoxygen saturation and parental incomes. Other traditional non-dependent variables were alsoanalysed and interestingly enough the functional score only detected around 18% of the riskfactors. This means that there are still many areas to know and understand [159-161].McCrindle [162] obtained information from 537 families (Parents Report Questionnaire) andpointed out the problems with pattern disturbances for attention and learning (around 46%) aswell as behavior problems (23%). The issue of neurodevelopment is controversial; recentinformation links it with fetal hemodynamic disorders and/or related with neonatal surgicalprocedures (circulatory bypass, aortic clamping and others). It is, anyway, a serious matter tobe concerned with [163,164].

ArrhythmiaThe lost or absence of the normal sinoatrial-ventricular synchrony is an undesirablecomplication for Fontan circulation. The development of atrial arrhythmias at mid- and longterm is a well-known factor for morbi-mortality; they are more prevalent in atrio-pulmonaryanastomosis (up to 60%) in regard to cavo-pulmonary techniques (between 10-30%), with anannual incidence between 4 to 15%. They can be at slow rate (sinus node dysfunction,junctional rhythm and complete AV block) or at a fast rate (intra-atrial re-entrant tachycardia,focal atrial tachycardia, atrial flutter and atrial fibrillation). The variable associated to theseatrial arrhythmia are: severe dilatation of the right atrium, length of follow up, older age atoperation, heterotaxy syndrome, severe AV regurgitation and previous bradi-arrhythmias.Altogether they induce a marked hemodynamic instability of the fragile univentricularcirculation, ventricular dysfunction, thromboembolism, reduction of the quality of life,several hospitalizations and, are particularly well-known causes of sudden death. As a result itis mandatory for prompt therapeutic actions and hemodynamic investigation and/orexhaustive diagnosis by imaging to detect disorders that could be potentially repairable byinterventional cardiology (obstructions along the Fontan pathways) or by surgery [165-169].The sinus node dysfunction can be observed in the preoperative period (7%) but there is anincrement in the staged Fontan (between 10-15% in the postoperative Hemi Fontan or BDGS)

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due to potential lesion of the sinus node [170,171]. Some authors claim major incidences withthe lateral tunnel (22%), others, on the contrary, do not detect significant differences; also, theintra/extra techniques with less atrial sutures seems to be a better approach. Even if somepatients recover the sinus rhythm inter-stage or post Fontan, in the vast majority the problempersists and even 10-13% of patients require a definitive pacemaker. The junctional rhythm absence of sinus rhythm is considered to be a risk factor for tachyarrhythmia and fibrotichepatic lesion. The tachyarrhythmias are prevalent and the most common (75%) is the intraatrial tachycardia due to macro re-entrant circuits, usually complex and/or numerous. It isfollowed in frequency by tachycardia caused by ectopic focus in 15%; atrial flutter and atrialfibrillation are reported mainly in adult patients and is a kind of arrhythmia often present inpatients sent for surgical conversion. There are no significant differences in the incidence ofintra-atrial tachycardia between the lateral tunnel and external conduit. Recently, amulticenter trial analysed the occurrence of arrhythmia (defined as the need of treatment atthe time of onset) in 1271 patients divided into two groups: A) intracardiac Fontan (602 pts)and B) extracardiac Fontan (669 pts). The incidence of bradyarrhythmias were: earlypostoperative 4% in group A and 11% in group B, late outcome 18% in group A and 9% ingroup B. In regards to tachyarrhythmia: early postoperative 5% in group A and 11% in groupB, late outcome 10% in group A and 3% in group B. The follow up was longer in group A(average 9.2 years) in respect to group B (average 4.7 years) [172,173].FIGURE 2.-

Different types of complications

COLLATERAL VEINTO LEFT ATRIUM

DECC

stenosisLA

RIGHT PULMONARYVEIN COMPRESSION

HEPATICCIRRHOSIS

thrombusright atrium

VARICOSE

IVC

Figure 2. Different types of complications.

The usually protocol to safely perform an electrical cardioversion is a useful form of

acute therapy to immediately improve the hemodynamic instability; on the other hand, antiarrhythmic drugs such as sotalol, propafenone, and beta blockers can appropriately control theheart rate but only between 20-30% of patients resolve the problem. The immediate successwith the ablation by catheterization reaches 70-80% but new arrhythmias reappear early inmore than half of the patients in spite of performing procedures with new techniques of 3Dmapping. Another treatment reported for arrhythmia control in Fontan patients is the differentand sophisticated pacing modalities. In this sense, and considering that the viability of the

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venous access to atriums is limited in the external conduit, preventive epicardial

atrioventricular leads are routinely implanted in Fontan second stage to avoid new minithoracotomy. The APa or LT conversion to ECC with surgery for the concomitant arrhythmia(right atrial maze for intra-atrial tachycardia and left mode for patients with fibrillation)drastically reduces the incidence of arrhythmia even if there is a recurrence of 15% reportedin the last type. This therapeutic approach is a good alternative that, in specialized centers,offers satisfactory results with low mortality even if around 6-8% will require heart transplant[174-176]

Protein-Losing EnteropathyThis is a serious, limiting and active clinical condition which etiopathogenesis,although not fully elucidated, is assumed to be multifactorial, interacting hemodynamic andinflammatory factors. It is hypothesized that chronic low cardiac output induces an increaseof the splanchnic arterial resistance (determined by the Doppler technique at the superiormesenteric artery and celiac artery), regional phenomena that, together with the increasedinfra-diaphragmatic systemic venous pressure, place in action as a cascade; inflammatoryfactors that slowly, silently and gradually will injury the integrity of the intestinal mucosae.This condition may be present in patients with any type of Fontan design and can be either inthe early as well as the late follow up. The average interval between the Fontan procedure andthe clinical onset of this syndrome is between 3.7 years and 8.6 years (with a range of 0.3 and19 years post Fontan), with a cumulative risk at 10 years of 13.4% [177-180]The variables associated with this syndrome are non-LV ventricular morphology,immediate post-operative renal failure, long cardiopulmonary bypass time and hospital stayand high end-diastolic ventricular pressure. It is characterized by a significant enteral loss ofplasmatic protein with a long half-life and the diagnosis (in the absence of hepatic or renalfailure) is done with the finding of hypoalbuminemia (< 3 gr) and a high quantity of alfa-1Antitrypsin in a 24-hour stool clearance test. Other remarkable laboratory findings (by theway similar to other causes of PLE) are: reduction of immunoglobulin IgG, IgM and IgA-,lymphocytopenia (reduction of lymphocytes CD4 and B), elevated proinflammatorycytokines (tumor necrosis factor-alpha, PCR and interferon-y), hypocalcaemia and alteredprothrombotic factors such as anti-thrombin III, proteins C and S. Intestinal mucosaelymphangiectasis confirmed by biopsy and histological examinations were observed in gastricendoscopies [181].Clinically there is edema, abdominal distension and ascites, pleural and/or pericardialeffusion, occasional or chronic diarrhea and finally malnutrition if the syndrome persists.Different pharmacological stratagems have been attempted with partial success: angiotensingconverting-enzyme inhibitors, steroids, high molecular weight heparin (to alleviate thecellular injury of the intestinal membrane), parenteral albumin, pulmonary vasodilators andspecific diet (medium-chain triglycerides). If there is a source amenable to be repaired it isdesirable to do it by catheter intervention: to enlarge obstructions present in Fontan circuit orcreate a fenestration, occlusion of aortopulmonary collaterals or overlooked and pervioussystemic-pulmonary shunts, atrioventricular pacing and resynchrony (in bradyarrhythmias).Of course it will be better off to convert the APa to cavopulmonary or heart transplant. The

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multicenter trial done by Mertens [178] proved that half of the patients will be dead in 5 yearsand will survive, only 20%, at 10 years if the syndrome is not solved. Any kind of lesionsubject that can be fixed must be repaired either by cardiac catheterization (desirable) or bysurgery. An important issue is the bone demineralization, a condition that happens in childrenand adolescents secondary to steroid therapy or related to the underlying abnormal Fontanhemodynamic (abnormal osteoblasts function). A bone densitometry scan is a study to beperformed periodically and measurement of osteoblast function biomarkers is mandatory[182].

Plastic BronchitisAn infrequent but extremely serious complication is the appearance of pulmonary distressdue to an obstructed airway by fibrinomucoid and cellular casts considered to be aconsequence of abnormal lymphatic fluid drainage even if some other factors are alsoincriminated in this problem. Plastic bronchitis is a potentially fatal condition that begins withcough, dyspnea and expectoration (the material mimic the bronchial shape), sometimesrecurrent, with regional atelectasis and it may progress to severe respiratory distress, evenleading to death. An incidence of < 3% is reported, present in any form of surgical Fontancircuit design and at mid or long term follow up. Its pathogenesis and physiopathology areconsidered to be multifactorial and in some aspects similar to those that originate the proteinlosing enteropathy: pro-inflammatory phenomena, defined immune phenotype, increase of thesystemic venous pressure, and low cardiac output, a possible role of genetic factors still to bedetermined. Different therapeutic strategies have been applied in relation to the clinicalseverity of the problem; therapy must be focused on solving the pulmonary obstruction and toimmediately determine the anatomy and physiology of the Fontan circuit. Having been tried,with variable rates of success at midterm: bronchoalveolar lavage, high frequency ventilation,steroids, aerosolized urokinase or tissue plasminogen activator, pulmonary vasodilators,Fontan fenestration, atrial pacing and heart transplant. Neutrophils, eosinophil, macrophages,and B lymphocytes were identified in cast samples; there were only fewer T lymphocytes.Fibrin was an abundant protein in the cast proteome. Histone H4 was also abundant and byimmunofluorescence microscopy was demonstrated to be mostly extracellular. The cytokineprofile of plastic bronchitis casts was proinflammatory. The cast formation cannot beexplained simply by lymph leak into the airways as they are composed of fibrin and arecellular and inflammatory in nature. Consequences of cellular necrosis including extracellularhistones and, the apparent low number of T cells, indicates that a derangement ininflammation resolution likely contributes to cast [183-188].

ThromboembolismBoth, thrombus formation and embolism, present either in the early or late follow up, arenot infrequent and could be present in 20-30% of survivors. Even if this percentage is notsufficiently convincing it is estimated that between 13-17% of patients can have a silentthrombus in some part of the Fontan pathway or even pulmonary embolism without any

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clinical manifestation. The stasis and systemic venous hypertension, the slow circulatoryvelocity, arrhythmias, prosthetic material in the venous circuit, presence of cul-de-sac, olderage at Fontan, procoagulant hematological disorders (antithrombin III, protein S and proteinC reduction, platelet reactivity), and non-antiplatelet treatment, are some of the well-knownrisk factors. The silent pulmonary thromboembolism impacts in a negative way on thepulmonary arteriolar resistance (increased resistance and emphasizing the chronic Fontan lowoutput), if it is especially massive should potentially be, the cause of sudden death. It has beenpointed out in the literature that systemic embolism can affect the neurological area (stroke),coronary system or some other areas; the origin can be founded at the APa level (arrhythmia),ventricular myocardium (significant systolic dysfunction), ligated pulmonary trunk (thrombusseated between the cul-de-sac and the pulmonary valve close to the systemic circuit), also thesystemic embolic phenomena was described in patients with a patent fenestration. Anyhow,the coagulation algorithms are currently under debate as there are many arguments for andagainst preventive anticoagulation; nevertheless the common tendency, particularly in adultpatients, is to keep a prophylactic antithrombotic therapy and to replace it with warfarin oracenocumarol in a thromboembolic episode. An issue to be of concern is the presence ofvaricose syndrome in adolescents or adults probably due to the combination of venousobstruction due to previous cardiac catheterization and the increase of systemic venouspressure [190-195].

Liver DysfunctionUsually upon physical examination, there is hepatomegaly secondary to venouscongestion in any type of Fontan circuit. Hepatic dysfunction, increased enzymes andcoagulation conditions are not infrequent, in fact more than 50% of patients have disorders ofthis kind yet it has been indicated that, in some cases, there is a fluctuation in serial lab tests;the length of follow up is a risk factor for this condition. More recently attention has beenfocused on the slow and progressive evolution toward fibrosis, cirrhosis and/or hepatoma,with different degrees of clinical manifestation. This progression to severe and limitinghepatic disease has not been fully understood. Among the identified mechanisms are not onlychronic hepatic congestion but also regional alterations of the hepato-splachnic systemresistance or insult, or hepatic injuries in pre Fontan stage. In any case, these observationsreinforce the necessity of a multidisciplinary team for follow up. Close and frequentsurveillance of the liver, using different diagnostic tools (Doppler flow pattern of portal andhepatic veins and arteries, magnetic resonance imaging, multi-sliced TAC) in some selectedcases the possibility of liver biopsy could be considered. The relevance of hepatic problemcan be noted in the need exceptional but already indicated for a particular patient havingan indication for heart and liver transplantation [196-199].

Cyanosis and Collateral Venous Circulation

The vast majority of patients have an oxygen arterial saturation not less than 92-95%;values below that level must be investigated as to the aetiology of the desaturation. Generally

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they are due to: intended surgical fenestration, residual interatrial communication (leaks),collateral systemic veins from infra/supra diaphragmatic origin that connect with the leftatrium or pulmonary vein, arteriovenous pulmonary malformations or intrinsic pulmonarypathology (restrictive physiology due to thoracic deformities, diaphragmatic palsy,pneumonia, pulmonary embolism). In the pathogenesis of the arteriovenous pulmonarymalformations, the absence of hepatic flow (hepatic factor) in the pulmonary circuit play arole, so this disease is more prevalent in patients with classic Glenn, in heterotaxy syndromewith intra/extrahepatic porto-systemic shunt, or operated on with the Kawashima technique,and also in a suboptimal Fontan circuit design (unbalanced pulmonary flow distribution). Inselected cases (with detailed hemodynamic evaluation to pondering pros and cons benefit/risk), a good deal of these permeable vascular anomalies or residual localized shuntscan be occluded with interventional catheterization as long as collaterals are not due to aneeded leakage mechanism for elevated venous pressure. The catheter occlusion of thesurgical fenestration is still controversial; some groups advocate the closure in theirmanagement protocol, on the other hand it is considered that the open fenestration forlifelong is for the patients safety [76,200-202]

Aortopulmonary CollateralsAfter BDGS or Fontan completion, the presence of aortopulmonary collaterals isconsidered a risk factor to influence the perioperative outcome. It is not known if thiscondition appears to compensate for the low systemic cardiac output; in any case controversypersists about the clinical or hemodynamic impact. The benefit of coil embolization isadvocated for different investigators, but a practice variation exists between centers. The leftto-right shunt that the aortopulmonary collaterals produce can be measured accurately by noninvasive phase-contrast MRI, and then the indication of coiling intervention can be adjusted[203,204].

Heart FailureAs the time of follow up passes by, some patients develop heart failure recognizable byperipheral edema, ventricular, renal or hepatic dysfunction. Around 30% of the patients havereduced systolic function measured by echocardiography or magnetic resonance: myocardialregional asynchrony, abnormal ventriculo-arterial coupling, atrioventricular electricaldisturbances, incoordinate relaxation and diminished beta-adrenergic reserves related tolimited preload, are some of the observations reported. Even a generalized approach withinter-centers variation, the conventional therapy (afterload inhibitors, beta blockers) isinconsistent. Diuretics and aldosterone antagonists are required and frequently used withsuccess for the treatment of Fontan failure. In selected cases, anecdotally, resynchronizationhas been used with beneficial results. The RV, in the setting of the HLHS, acts as a singlechamber and its ability to pump after Fontan completion will be prevalent in the next years;therefore, it will be very interesting to watch their function in the long-term follow-up [93,205-207].

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Mechanical Assisted Devices Heart Transplant

Some patients with failing/failed Fontan require advanced cardiac support due tounsuccessful conventional therapeutic attempts. In the last few years ventricular assist devices(VADs) as a bridge to heart transplant have been used with increasing frequency not only inadults but also in children. Orthotopic heart transplant is the latest opportunity of effectivetreatment or solution for these patients even though the indication and timing are underdebate. Most studies report a perioperative transplant mortality of 30% and a 50% survivalestimated at 10 years [208, 209].

Fontan Procedure in Adults

The Fontan operation is possible in adult patients (>18 years old). The analysed reportsinclude the 3 types of surgical technique applied to children. The vast majority of patientshave a previous palliation with aorto-pulmonary or cavopulmonary shunts. The hemodynamicstudy before the Fontan operation is mandatory and patient selection is very strict to avoidincluding patients with risk factors. The creation of fenestration is variable, even minority.Hospital mortality is reported below 10%. Two aspects are relevant: 1) arrhythmias arefrequent pre and post-operatively and 2) albeit the functional state measured by NYHA scalein survivors is better than preoperative, an early decline of the ventricular function has beennoticed. The life survival is 65% at 15 years with free-from-operations of 80% at 15 years[210-212].

Mario Cazzaniga and Renata Revel-Chion

The FutureNumerous researchers realize the adversities and doubts that lurk in the long-termlongevity of the univentricular model with any technique used. The failure of traditionalmedical care leads us to promote the heart transplant in addition with liver transplantation insome cases - as the only one effective and definitive treatment of the failing or failed Fontan.Some clues can be derived from the following information: 1) the incidence of complicationsincrease when the univentricular circulation is completed if compared to the partial model(BDGS) [213,214] 2) the permeable fenestration at least at mid-term (increase the cardiacoutput and reduce the systemic venous pressure) offers better functional expectations even atthe cost of maintaining some degree of hypoxemia [200], 3) the progressive endothelialdysfunction with unfavorable multi-organ impact is a reality [215], at the pulmonary levelwhere the non-pulsatile flow promotes a slow and insidious rise of the vascular resistance evidence of vascular disease after cardiac transplant in Fontan patients [216] and disorder inthe modulation and release of endothelin-1 and nitric oxide among other factors, or, at thelevel of other systemic pulsatile subsystems (splanchnic bed) where the regional arteriolarresistance increases secondary to chronic low cardiac output, 4) the promising chronictherapy with 5-phosphodiesterse inhibitors sildenafil with well-known benefits associatedwith improved exercise performance [217], 5) computation models performed in theexperimental field demonstrated flow abnormalities in the TCPC surgical pathways at rest orat computer-generated stimulus; an optimization of the system design (Y-shaped form ordirect connection inferior vena cava-pulmonary artery to obtain a more equivalent pulmonaryflow distribution) by means of the bio-engineers based on imaging patient-specificsimulations is needed [218], and 6) innovative experts have designed new devices forpotential implant in the extra cardiac conduit with the view to actively promote the systemicvenous circulation to the pulmonary circuit with the purpose of increasing the cardiac output(mimics a subpulmonary ventricle) yet without clinical application [219-221].There are several unsolved challenges in the next decades that will require thecontribution of some other scientific disciplines for a better understanding of the nature of thedifferent clinical disorders as well as the potential adjusted-treatment. These are only some ofthe problems to be solved: a) to elucidate if the clinical pictures depend on compensatoryadjustments of the univentricular physiology or if they are only pathological consequences ofthe procedures, b) to identify the molecular starting point responsible of the pulmonaryarteriovenous malformations (the so-called circulating hepatic factors) as liable to inducepotential misbalance between pro and antiangiogenic signals and/or find the link betweenthose vascular malformations and bone morphogenetic protein-9 (222-225), c) to define thelink between exogenous growth hormone given to Fontan patients with short stature and theincrease in arteriovenous malformations or worst PLE syndrome (226), and d) a possibleapproach with new molecular therapy and cell replacement to repair or replace abnormaltissues during morphogenesis (227,228). Perhaps only few questions but they merge the needof a multidisciplinary approach to this new generation of survivors. Are we doing correctly orare we just leading a complex pathway with an intricate end?. Many difficult questions to beanswered yet and they are on the air.The concept of multidisciplinary team units expert in the knowledge and management ofpatients with UH physiology whom survive longer is imperative, not only to face the relatedcardiovascular problems but also to give support and care in fields like non-cardiac surgery,

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pregnancy, insurances, employment, psychological support and social activities

(135,137,200,229-234). Therefore, what it has been reported here just support our adherenceto what forward-looking physiologists advised already centuries ago: the subpulmonary rightventricle is essential for the human life.

Alejandra Villa1* and Marisa Di Santo2,

AbstractRestrictive cardiomyopathy is a rare disease in childhood characterized byventricular diastolic dysfunction usually with preserved systolic function, with aprogressive clinical course and poor outcome. This chapter reviews the definition,epidemiology, genetics, natural history, clinical presentation, role of diagnostic tools,outcome, and current management of pediatric populations with this uncommon diseasebased on our clinical experience and literature studies. Restrictive cardiomyopathy inchildhood is a rare entity with high mortality rates that still arises controversy around itsdefinition and treatment. The stratification of risk factors for sudden death, cardiacfailure, thromboembolic events and increase in pulmonary vascular resistance requiresprospective longitudinal studies with large pediatric populations in order to acquire betterknowledge of the course and outcome of this disease. The identification of specificgenetic mutations is paving the way for a better understanding of the molecular pathologyof restrictive disorders. This line of research will most probably lead to the design of newtherapies that can delay or reduce the need for heart transplant.

IntroductionCardiomyopathies (CM) are a heterogeneous group of diseases. There are manyclassifications in the literature and sometimes they are contradictory. One of theclassifications that is important to mention is the one outlined by The European Society of*

E-mail: avilla@arnet.com.ar.E-mail: mdisanto@ffavaloro.org.

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Cardiology. They proposed a clinically oriented classification system in which heart muscledisorders are grouped according to ventricular morphology and function. This classificationhas become the most useful method for diagnosing and describing a cardiomyopathy. Thus, acardiomyopathy is defined as a myocardial disorder in which the heart muscle is structurallyand functionally abnormal, in the absence of coronary artery disease, hypertension, valvulardisease and congenital heart disease, sufficient to cause the observed myocardial abnormality.In this chapter we will focus on the restrictive cardiomyopathy (RCM), which is a diseaseof the myocardium with diastolic dysfunction as the principal abnormality specifically,restricted ventricular filling [1].

Definition and Epidemiology

The World Health Organization (WHO) defines RCM as a myocardial diseasecharacterized by restrictive filling and reduced diastolic volume of either or both ventricleswith normal or near-normal systolic function and wall thickness. But why is still difficult indaily practice to classify patients with RCM?1. Probably because of the use by the American Heart Association (AHA) and theWHO of such terms of poor specificity as mild hypertrophy and near normaldiastolic volume, which seem to be left to individual medical judgment as to whatexactly is mild or near normal.2. Because the term restrictive cardiomyopathy is based on the description of theventricular physiology and there are various conditions that can affect the filling ofthe heart, such as amyloidosis, sarcoidosis, carcinoid heart disease, scleroderma,anthracycline toxicity or other morphologic entities like hypertrophiccardiomyopathy (HCM), dilated (DCM) or left ventricular non-compaction [2].3. Because although histology helps identifying primary and secondary forms of thedisease, it is normally non-distinctive and can show normal findings or non-specificdegenerative changes, including myocyte hypertrophy, disarray, a degree ofinterstitial fibrosis, and as much as 40% of cases look like hypertrophiccardiomyopathies (HCM).RCM is a rare form of cardiomyopathy accounting for 2.55% of all idiopathiccardiomyopathies in childhood. [1-3]Although the exact prevalence is unknown.A few series with limited number of patients have been published documenting theclinical course after the diagnosis of RCM in childhood. Due to the small size of patientpopulation in these studies, its pathogenesis, natural history, and treatment are still object ofresearch. Some investigators have divided RCM into the following subtypes: (1) purerestrictive cardiomyopathy; (2) hypertrophic-restrictive cardiomyopathy, and (3) mildlydilated restrictive cardiomyopathy. [4] This classification arises because even thoughrestrictive cardiomyopathy (RCM) has been subclassified individually, evidence exists forconsiderable overlap between this entity and hypertrophic cardiomyopathy (HCM).Moreover, in the familial type of RCM, some family members present with mutationsexpressed as classic hypertrophic cardiomyopathy. [5] The prevalence of pure familial versus

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sporadic RCM is not known.The first sarcomeric protein for which mutations have beenassociated with restrictive cardiomyopathy is human cardiac troponin I (TNNI). The locationof the mutation within different functional domains of TNNI results in different clinicalphenotypes. RCM has also been associated with the intermediate filament protein Desminabnormalities. The mechanism(s) by which these mutations affect muscle contraction are stillbeing investigated [6].

GeneticThe last consensus of 2006 by the American Heart Association (AHA) [7] developedContemporary Definitions and a Classification of the Cardiomyopathies. They list the knowncauses of RCM, however, in the pediatric population in most no specific cause has beenidentified with increasing reports of specific gene mutations in this age group.In the past two decades, advances in molecular analysis have pointed out the importantrole of mutations in genes encoding sarcomeric proteins associated with RCM [8] and,although less frequent, with non-sarcomeric proteins such as desmin.

Sarcomeric Protein Disease and RCM

In the current era genetic investigations have revealed that RCM forms part of thehereditary sarcomeric contractile protein disease spectrum [5-8].The most common mutations in the sarcomeric protein encoding gene were identified inTNNI3 Beta-myosin heavy chain (MYH7), Troponin 2(TNNT2), and -Cardiac actin (ACTC).It is necessary to briefly consider the normal regulation of muscle contraction [9].The troponin complex, which is composed of three subunits, troponin C (TNNC),troponin I, and troponin T (TNNT), is located within the thin muscle filament, and itsfunction is to control the interaction between the thick and thin filament during musclecontraction and relaxation, dependent on the intracellular concentration of Ca2+.Troponin I binds to actin-tropomyosin and prevents muscle contraction by inhibitingactomyosin activity. This inhibitory effect is reversed by troponin C following binding ofCa2+, which introduces changes in the entire troponin complex. The myosin head is bindingto actin and ATP to myosin, causing displacement of the myosin head along the thin filamentand ATP hydrolysis, leading to muscle contraction. The mutations in sarcomeric proteinshave the potential to cause alterations in thin muscle filament with an increase in Ca2+concentration triggering disturbances in contraction, cardiomyopathy, arrhythmias, andsudden cardiac death (SCD) [10].Specially mutations in troponin have been identified causing RCM. The subunit TNNTacts modulating actomyosin ATPase activity, Ca2 sensitivity of contraction, and maximalforcein muscle contraction, one of the main factors necessary for normal contraction.Sarcomeric protein gene mutations in the cardiac troponin I gene (TNNI3), in the troponin T(TNNT2), and -Cardiac actin were the first mutations identified associated with RCM. [11]No mutation in the gene encoding for TNNC has been detected yet. [11] Histopathology from

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explanted hearts with a TNNT2 mutation shows interstitial fibrosis and myocyte disarray withloss of sarcomeric architecture.The TNNT gene can express four different isoforms: isoform 1 is predominant in fetalhearts and isoform 3 in adult hearts, being the main difference between them the absence ofexon 5 from the N-terminal domain of the adult isoform 3 present in the fetal heart [12].In this aspect fetal troponin isoforms in the developing heart revealed a protective role inmaintenance of normal physiological parameters during stress situations, such as acidosis.[12] The switch of TNNI can be seen on the fourth day after birth and goes on until dayfourteen. Mutations in gene encoding for troponin I may produce serious effects just afterbirth explaining the symptoms and aggressive course.Pinto et al. describe the protective role of fetal troponin (TN) isoforms and the way theyrescue increased Ca2 sensitivity produced by a TNNT gene mutation in RCM, preventinglethality of the fetus during gestation [12].During the development of the heart, TNNT is expressed continuously and thus, it isexpected that RCM may manifest at the end of gestation or produce spontaneous abortions,which may explain why the conditions have not been completely identified yet. More than 20mutations linked to RCM [10] have been reported in the genes of cardiac desmin, actin,myosin heavy chain, T troponin (TNNT), and troponin I (TNNI) compared to more than 900mutations reported for HCM. [6] Nevertheless, several gene mutations in sarcomeric proteinshave been reported in association with RCM, but they may cause the hypertrophic and dilatedcardiomyopathy phenotype in some family members, showing a phenotypic overlap causedby the same underlying gene alteration [13].Mogensen et al. identified a novel mutation in troponin I in a large family in whichseveral individuals were affected by either hypertrophic or restrictive cardiomyopathy. Theindex case was an 11-year-old boy with IC. [8] The members of the family had HCM withonly mild to moderate hypertrophy and the majority presented with enlarged atria andevidence of restrictive ventricular filling, suggesting phenotypic variability of the samemutation [8].In a follow-up study by Mogensen et al. [8] and Kubo et al. [14] reported a group ofadults with HCM and a restrictive phenotype. Eight of 15 patients had identifiable mutationsof the sarcomeric genes, four in - myosin heavy chain gene and four in troponin I. All eightpatients had a bad prognosis.Kaski et al. published a series of 12 pediatric patients with RCM, four of whom had apositive family history for cardiomyopathy, but with variable phenotypes including noncompaction cardiomyopathy and RCM. [11] The mutations identified were located in thetroponin I (TNNI3), troponin T (TNNT2), and cardiac alpha-actin (ACTC) genes.The diversity in phenotypic features of troponin expression in family members suggeststhat both genetic and environmental factors may play a role in the disease expression [15].Alterations in other contractile proteins, such as myosin, present a genotypicphenotypic overlap as well. This has been shown in a report by Olson et al. [16] whodescribed a mutation in myosin light chain causing cardiomyopathy with mild hypertrophywith a restrictive physiology which was inherited in an autosomal recessive manner. Theindex case was a boy with two older brothers who had cardiomyopathies with dilated atriaand died due to thromboembolic complications. Clinically non-affected family members wereheterozygotes or lacked the mutant allele.

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Ware et al. described a -myosin heavy chain mutation in an infant with RCM whoreceived a heart transplant. [10] These -myosin heavy chain mutations account forapproximately 40 % of the mutations found in adults with HCM, but are infrequent inchildren. Phenotypicoverlap of RCM and non-compaction cardiomyopathy has also beenobserved and thus, this type of cardiomyopathy should also be looked for in children fromfamilies with RCM [17-19].

Non-Sarcomeric Protein Disease and RCM

Additionally to those of the sarcomeric proteins, cell structures of other proteins may bealtered. Some examples are titin (TTN) and desmin mutations. [20, 21] Peled et al. firstshowed that TTN mutations may cause RCM. [20] The giant filament TTN is a determinantof a resting tension of the sarcomere and the study provides genetic evidence for its crucialrole in diastolic function based on a family with six affected individuals between 12 and 35years of age. Eighteen candidate genes for the alteration were studied. Sequence analysisidentified a novel mutation in exon 266 of the TTN gene, resulting in a tyrosine by cysteinesubstitution p.Y7621C affects a highly preserved region of the protein within the fibronectin3 domain, belonging to the A/I junction region of TTN [20].Desmin mutations have been described associated with RCM and conduction anomalies,including AV block, as well as skeletal myopathy. [22] Inheritance may be autosomaldominant, or the mutations may be sporadic [22, 23] however, no large cohort studies havebeen conducted in pediatric patients with RMC and thus, the role of the disease in childhoodremains to be determined [23, 24].Genetic alterations in the plasmatic proteins of transthyretin causing amyloidosisassociated with RMC have been found, but none of them in children. Coffin-Lowry syndromeis a disorder due to mutations of the RSK2 gene located on the X chromosome, Xp22.2.29,causing facial dysmorphism, low stature, progressive skeletal deformities, and RMC. [25]Emery-Dreifuss dystrophy is an emerin disorder of autosomal dominant inheritance caused bymutations in the gene encoding for lamin A and C on chromosome 1 q21.2 q21.3.31 andhas also been linked to chromosome Xq28.31. Both variants may produce cardiomyopathy,atrial and ventricular arrhythmias, conduction disturbances, and sudden death, however, therestrictive phenotype has not been reported [25].

PathophysiologyIn order to understand the pathophysiology of RCM we must briefly recall themechanism by which cardiomyocyte contraction is generated.The sarcomere is surrounded by a membrane system (sarcoplasmic reticulum). It isformed by myosin bands in the center separated on each side by actin filaments. At rest,myosin filaments are neatly surrounded by actin in a way both filaments coincide, thoughthey remain separate. That is so thanks to troponin and tropomyosin that form a complexaround the actin filaments preventing them from getting stuck to the myosin ones. Troponin isa complex. Each troponin is formed by 3 subunits:

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troponin C, has affinity for Ca2+.

When calcium concentration increases in sarcoplasm, it binds to troponin, causing

inhibition of the block caused by tropomyosin. Actin-tropomyiosin complex is hence formed,acting as a bridge. We must remember that Troponin is a complex formed by three subunits:troponin C, with affinity for calcium; troponin T, united to tropomyosin and troponin I, whichinhibits the formation of bridges between myosin and actin.When the bridge is formed the ATPase function on the myosin head is activated and ATPis dissociated in ADP+Pi (inorganic phosphorus), this process requires Mg2+. Whenphosphate leaves the myosin head it generates a rotation or movement of it causing the actinfilament to move along the myosin filament towards the center of the sarcomere, generating ashortening of the fiber [11].Alternatively, during diastole, Ca2+ levels decrease, troponin C dissociates allowingMg2+ to binds to C-terminals. This generates relaxation of the fiber, allowing the ventricularfilling to take place.Restrictive physiology is characterized by an abrupt cessation of ventricular filling inearly diastole, with minimal mid and late diastolic flow causing a dip-plateau pattern on theventricular pressure tracing. [26, 27] This typical pattern is the haemodynamic hallmark ofrestrictive cardiomyopathy. Why does this process occur? Any functional and structuraldefects in any of these troponin subunits may cause alterations in the Ca2 regulation ofmuscle contraction.The fibers containing RCM mutations show incapacity to fully relax, and this improperrelaxation is believed to be related to the high Ca2 sensitivity and the altered relaxationproperties of the fibers themselves. As Gomes et al. have demonstrated in an in vitro study,the mutations in TNNI3 associated with RCM show similar in vitro physiologicalcharacteristics as TNNI HCM mutations but with a greater increase in Ca2 sensitivity, higherlevels of basal force and higher levels of basal ATPase activity. Furthermore, mutations inTNNT2 have also been reported in association with infantile RCM. [9] and familial dilatedcardiomyopathy (DCM) [11].What determines the different expression of the same mutation is under study;environmental factors or other genetic factors could probably be involved. This ultimatelyresults in decreased compliance of the ventricle with development of atrial dilation with thetypical characteristics of normal systolic function, although with the progression of thedisease, this can be deteriorated, and increase pulmonary pressure and resistance.

Natural HistoryWhen we think of the natural history of RCM, we must bear in mind that it is aninfrequent disease, that the series published have a small sample size and that the number ofpatients that have subclinical RCM is unknown. Once the symptoms develop, morbidity andmortality are high.

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Denfield and coworkers stated that little is known about the causes and outcome of RCMin childhood. They described twelve cases of RCM and they concluded that the prognosis ofRCM is poor, since 33% of patients presented with embolic events, 75% of patients diedwithin 6.3 years, and within 1 to 4 years of diagnosis, patients developed a markedly elevatedpulmonary vascular resistance index. Therefore, they recommended that transplantationshould be considered early [28].Also, Cetta et al. [29] found that children with RCM who had symptoms of dyspnea andpulmonary venous congestion had the highest risk of death, and they suggested earlyconsideration of cardiac transplant.In our series of 36 patients, the survival rate was 86 months (IC 95%; 59113), and 43months in the case of children under 5 years of age (CI 95%; 3557). In a multivariateanalysis, the risk factors for poor prognosis were shortening fraction (SF)<28% and arelationship left atrium /aortic root (LA/AO) greater than 2.3. Only 2 patients presentedthrombosis and another 2 patients, signs of ischemia on Holter monitoring.If we compare RCM with other types of cardiomyopathies analyzed in the literature, wecan see that children with restrictive CM were younger at diagnosis and had a significantlyhigher pulmonary vascular resistance index (PVRI) [30].All studies in the literature agree that patients should be considered for orthotopic cardiactransplantation before the development of severe pulmonary hypertension, but patientselection criteria can be difficult to define. An elevated pre-transplant PVRI greater than 6U.m2, and transpulmonary gradient (TPG) >15 have historically been a contraindication forcardiac transplantation, since they are associated with an increased risk of posttransplantmortality and right heart failure [30].The development of new mechanical support options pre and post transplant plus the newset of drugs available for the treatment of pulmonary hypertension seem to have expanded thetherapy options. Hughes et al. [30] published a successful orthotopic cardiac transplantationwith a PVRI > 6 U.m2 in the presence of pulmonary reactivity, and they concluded thatpulmonary vascular reactivity may be a more important prognostic factor than the absoluteresistance index.Thus, we can conclude that RCM is a severe, progressive disease with a mortality rate ofup to 50% during the first 2 years after diagnosis. Children with a more chronic course showprogressive heart failure, risk for acute onset events such as dysrhythmias, stroke, and suddendeath. [31] Concerning this, Rivenes et al. reported a series of 18 patients; the patients at riskfor sudden death showed at presentation chest pain, syncope or both in the absence ofcongestive heart failure. Holter monitor evidence of ischemia predicted death within months.The authors proposed the use of b blockade, implantable cardioverter defibrillator (ICD)therapy, and listing for cardiac transplant [32].The natural history of RCM in childhood shows that it is a rare disorder with pooroutcome. The early detection and current development of new drugs and tools for thetreatment of cardiac failure and arrhythmias can probably contribute to changing the poorresults in the long term.

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Clinical ProfilePhysical ExaminationPhysical examination findings can be variable and indistinct; in patients who are onlymildly affected, standard studies may be normal. These studies usually evaluate the degree ofcongestion from the diastolic dysfunction of the affected ventricle. When the left ventricle isaffected, pulmonary edema, pulmonary hypertension and decreased myocardial reserve resultin reactive airway disease, recurrent lower respiratory tract infections, dyspnea on exertion,palpitations, syncope, sudden death or/and thromboembolic events [31-33].Mitral regurgitation and tricuspid insufficiency commonly develop over time. Thepresence of murmurs and S3 or S4 gallop rhythms are common, as well. With thedevelopment of pulmonary hypertension, S2 becomes louder. Right-side congestion isexpressed as hepatomegaly, jugular venous distention, and Kussmaul sign, either because ofright-side RCM or pulmonary hypertension secondary to left-side RCM. When the diseaseprogresses, patients present with peripheral edema, ascites and frank congestive heart failure.In our series, at diagnosis 27/36 patients (75%) were symptomatic: 13 presented clinicalsigns of left heart failure; 3 patients, right heart failure, and 11 had signs of global heartfailure.ElectrocardiogramThe electrocardiogram is abnormal in about 100% of cases, with frequent biatrialenlargement and nonspecific ST-T wave abnormalities (Figure 1). Right or left ventricularhypertrophy and also conduction abnormalities can be present, such as second degreeatrioventricular block (AV B) and complete heart block.The use of Holter monitoring as complementary study for the detection of arrhythmiasand ischemias is mandatory. Arrhythmias are not uncommon in RCM (approximately 15%),including atrial fibrillation, flutter, ectopic tachycardia and ventricular tachycardia [31].In our cohort, all 36 patients (100%) presented sinus rhythm and auricular hypertrophy,and 64.3% had alterations in repolarization. No ST-T wave abnormalities, signs of AVB, orconduction abnormalities were observed. Holter monitoring evidenced no arrhythmias orconduction abnormalities at the time of admission.Chest X-RayThe chest x-ray is usually abnormal, and with this simple test it is possible to suspectdiagnosis of the disease. Cardiomegaly secondary to atrial enlargement and venouscongestion are typical features of this pathology.In our study, the cardiothoracic ratio was >65% at the expense of atrial enlargement in allpatients; 42.7% presented alterations of the pulmonary flow due to passive congestion(Figure 2).

Cardiac CatheterizationThe elevated left or right ventricular end diastolic pressures and the classic pattern inpressure tracings, typical square root or dip-plateau pattern, help to confirm left or rightdiastolic dysfunction (Figure 3).Since noninvasive techniques have evolved and proved to be useful for hemodynamicassessment, the modern role of cardiac catheterization in restrictive cardiomyopathy is thedirect assessment of pulmonary hypertension and calculation of pulmonary vascularresistance. When resistance is high, pulmonary reactivity tests are fundamental to precludefrom orthotopic heart transplant. Endomyocardial biopsy can be helpful although it is notrisk-free [30].

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In our cohort, 18 patients underwent hemodynamic studies. The left atrial (LA) andpulmonary capillary pressure was 17 6 mmHg (range, 12-30 mmHg). Left atrialenlargement was observed in all patients. The mean pulmonary pressure was 34 6 mm Hg(range, 28-40 mm Hg). The left ventricular end diastolic pressure (LV) was 19 6 mm Hg(range, 12-30 mm Hg). Only 50% of patients showed the square root or dip-plateau pattern onthe left ventricular pressure. Angiography evidenced signs of diminished ventriculardistensibility.EchocardiographyRCM can be diagnosed with an echocardiogram based on the markedly dilated atria inthe absence of significant atrioventricular valve regurgitation.Systolic function is typically preserved, although some degree of systolic dysfunction hasbeen seen in some patients at presentation, and deterioration of systolic function over time hasalso been reported in children [34].Diastolic patterns present according to LV distensibility and it has been reported in theadult population that very symptomatic patients have restrictive mitral flow, the E wavepredominating over the A with a diastolic isovolumetric period of < 70 ms and E wavedeceleration time of generally< 100 ms.The left restrictive flow correlates with a pulmonary vein inflow [15] characterized by anincrease in the velocity of the pulmonary reversed A flow > 35cm/s and a duration of > 30msthan that of the mitral A flow when the LV end diastolic pressure is over 20-25 mmHg.A predominant antegrade diastolic flow without changes during the different phases ofthe respiratory cycle is seen as the left-sided filling is permanently increased [31].In the tricuspid valve restricted flow is observed which increases the E wave withinspiration, not more than 10% basal flow during apnea (unlike in constrictive pericarditis inwhich it is typically more than 15%), with a clearly shorter tricuspid flow deceleration timecompared to patients with constrictive pericarditis. Maximum velocity of tricuspidregurgitation is used for the estimation of pulmonary systolic pressure, which is generally

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high. Pulmonary pressure is often higher than 40mmHg while the pressure is lower inconstrictive pericarditis [34].In children, findings consistent with restrictive filling and increased left ventricular enddiastolic pressure include elevated mitral valve Doppler E/A ratios, short mitral decelerationtimes, increased pulmonary vein atrial reversal velocity, and duration and pulmonary veinatrial reversal duration greater than mitral A wave duration.Doppler echocardiography allows differentiation from constrictive pericarditis which,unlike restrictive cardiomyopathy, respiratory-phase changes in mitral, pulmonary vein, andsystemic vein inflow [35].In RCM, an inflow with a predominant antegrade diastolic flow throughout therespiratory cycle is found in the suprahepatic veins and in the superior vena cava.In the pulmonary and hepatic veins, the systolic is much higher than the diastolic flowvelocity. An increase in diastolic low inversion is seen in the hepatic veins during inspirationas well as an increase in the velocity and duration of atrial flow inversion in the pulmonaryveins.Tissue Doppler echocardiography has also proved to be useful for the differentiation ofRCM from constrictive pericarditis based on telediastolic mitral ring velocity or measuringthe gradient of posterior wall velocity [36, 37].The combined use of an averaged S' cutoff value <8 cm/s as well as an E' cutoff value <8at the lateral and septal MA demonstrated 93% sensitivity and 88% specificity for thediagnosis of RCM.Tissue E velocity of less than 0.8 cm/s has been described and a tissue E wave/mitral Ewave ratio of less than 0.11 strongly suggests restriction.The recently developed technique of the M color mode [38] is also useful for thedifferentiation of RCM from constrictive pericarditis. In the inflow an E and A wave similarto those on Doppler echocardiography are observed. In the restriction, baseline and totalpropagation velocity to the apex are markedly decreased (typically less than 0.45 cm/s) thebasal-apical return time is clearly prolonged compared to the values in constrictivepericarditis [38].In different studies in pediatric patients, it has been shown that the diastolic functiondescribed in cardiomyopathies in adults, including RCM, is not useful in children. Gewillinget al. state that in their series of six pediatric patients, the diastolic pattern behavior wasdifferent from the classical pattern in adults. The echocardiographic patterns werepseudonormal and not restrictive, showing an L wave [27].Newer echocardiographic techniques such as speckle-track imaging, velocity vectorimaging, can help differentiate constriction from restriction with high sensitivity andspecificity. [39] The results shown by Dragulescu et al. suggest that among thevariousdiastolic function (DF) echo parameters, mitral E wave deceleration time (DT), andleft atrial volume indexed to body surface area (LAVi) are likely to be the most useful in theevaluation of DF in children with CM. They conclude that isolated delayed relaxation is seenin only a minority of HCM patients and not in DCM or RCM. And these results suggest thatpediatric diastolic dysfunction (DD) does not follow the progression seen in adult patients andthat new diagnostic criteria are needed in children [40].In our series of 36 patients a greatly enlarged left atrial (LA) (X= 35 mm; range, 31 mm40 mm) was observed, with a significantly elevated aorta/left atrium (AO/LA) ratio (2.4 0.4) in all studies (Figure 4).

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Figure 4. Apical four- chamber echocardiographic view. The right atrium and the left atrium are bothseen to be markedly enlarged. The right and left ventricle are normal in size.

The LV diastolic end diameter and posterior wall thickness were normal (Z score < 2) in27/36 patients. Patients in the group with a mixed phenotype presented with bi-ventricularhypertrophy in seven patients and LV hypertrophy in two patients.The evaluation of the systolic function of the LV showed a shortening fraction (SF) of34% (range, 28-40%). Thirty patients presented with no or very mild valve insufficiency.In the evaluation of ventricular filling three patterns of relaxation were identified:(Figure 5)

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1. Restrictive pattern: seen in 19 patients, with an E/A relaxation ratio greater than 2.2. Pseudonormalized pattern: seen in 12 patients, with an E/A relaxation ratio less thanor equal to 2.3. In five patients a pattern with three diastolic waves (E, L and A)was observed.Cardiac Magnetic ResonanceCMR is helpful because it can detect the anatomy of any pericardial thickening, thehaemodynamics of constriction and any abnormality of the underlying myocardium. Thepericardium can be delineated on black-blood imaging and inflammation can be imaged usinglate gadolinium enhancement (LEG) (owing to the increased extracellular space associatedwith oedema and breakdown of cell walls). Tethering to underlying myocardium and lack ofslippage can be seen using tagging, and real-time cine-CMR [19] may show ventricularventricular interaction (compression of the left ventricle by the right ventricle during deepinspiration), which is a hallmark of constriction.Therapeutic OptionsPreventing arrhythmias, sudden death and selecting the right candidates for cardiactransplantation instead of only offering to treat heart failure symptoms have become thepresent day therapeutic challenges for the cardiologist. Even though the diastolic alterationsthat these patients present generate pulmonary venous or systemic congestion and can betreated with diuretics, the use of these medications must be controlled, since they produce lowcardiac output and require an adequate preload in order to preserve it. Spironolactone is thedrug of choice and can be used as single medication or together with furosemide at low doses.When the disease progresses, systolic dysfunction appears, but unlike the case of otherpathologies, the use of vasodilators in RCM should be controlled, since these patients areunable to increase the ejection volume and this can lead to hypotension without increase incardiac output. [41]Concerning the patients that present with signs of ischemia as evidenced in the ECG orHolter monitor, beta blockers have been used, however controversial, provided they do notshow sinus node disease or AV block.In the case of patients with sudden cardiac events, such as sudden death episode, syncopeor arrhythmias, the implantation of implantable cardioverter-defibrillators (ICDs) should beconsidered. In addition, different authors have described the development of AV block.Walsh et al. [41] showed a series of 17 patients that presented sudden events with theresulting death in 4 of them, 2 due to acute AV block. They observed that the patients whoshowed these events had a prolonged PR and a QRS of longer duration [42].In our series of 36 patients with RCM, during the follow-up 2 patients presented AVblock and they received a pacemaker. Two patients showed ventricular tachycardia (VT) andthey died. One patient developed auricular flutter and was put under amiodarone therapy.Two patients that presented with signs of ischemia and frequent ventricular extrasystoles asevidenced in Holter monitoring received antiarrhythmic medication.Children with RCM have a higher risk of developing thromboembolic events; the seriespublished in the literature show between 12% and 32% of occurrence. According to thereview by Chen et al., the risk factors for such events are: LA with Z score >3 and reducedsystolic function. This group of patients should receive warfarin, and those with preserved

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systolic function should receive aspirin. Patients with arrhythmias should also beanticoagulated [43].Heart transplant is the definitive treatment of choice for RCM, since survival rates andquality of life post transplant far exceed the natural history of the pathology. But when shouldtransplant be the option? Consensus as to when it should be indicated has only been reachedwhen considering patients that show severe signs of cardiac failure or a high pulmonarypressure and pulmonary vascular resistance, although some physicians enroll their patients onan early list for transplant [44].But the greatest dilemma around this pathology arises when patients show mildsymptoms or they are asymptomatic. What should be done in those cases? Webber et al.showed in their review that survival rates since diagnosis were almost the same in the case ofpatients that presented with symptoms or syncope as with those who were asymptomatic atdiagnosis. They did not find any statistical correlation between pulmonary vascular resistanceindex (PVRI) and survival in their cohort. The authors suggest that the presence of cardiacsymptoms should not be the key factor to determine when to enroll patients fortransplantation, as is usually the case in other types of pediatric cardiomyopathies [45].Furthermore, there is another controversy around transplantation: what levels ofpulmonary vascular resistance (PVR) should a patient have to be listed for heart orcardiopulmonary transplant? A pulmonary vascular resistance index greater than 6 Woodunits (WU) m2 is often considered as a contraindication for heart transplant because there isa marked increase in PVR that can lead to right ventricular dysfunction during thepostoperative time [46, 47].However, Bograd et al. reported data on the evaluation of a group of patients with RCMand PVR> 6 UW, with a mortality rate of 86% per year and normalization of PVR inapproximately 3 months. Nevertheless, these patients required extracorporeal membraneoxygenation (ECMO) after heart transplant [47, 48].In our experience, 6 out of 45 patients with RCM were transplanted and 3 remain on awaiting list. Three of the 6 transplanted patients presented PVR> = 6 UW/m, with severeglobal heart failure; they received ventricular assistance (Berlin Heart) prior to beingtransplanted. Survival after one year of diagnosis was 83.3% for the 6 patients. We believethese patients must be closely controlled in order to follow the progression of PVR. Ourpatients are enrolled for transplantation when they present heart failure of elevated pulmonarypressure, since the lack of donors in our country is an important problem [49].

DiscussionRCM in children is an infrequent disease accounting for 2.5-5% of all pediatriccardiomyopathies. The clinical prognosis of RCM in children is very different from the adultphenotype. Survival rate two years after diagnosis is 50%.In a study published by our team in 2002, we observed that the survival rate of ourpopulation was 42.8% during a mean follow-up of 4 years, and 13.8% of the cohort had afamily history of cardiomyopathies [50].The Pediatric Cardiomyopathy Registry (PCMR) analysis showed 152 cases of RCM,which accounts for 4.5% of all cardiomyopathies identified under PCMR. A fourth of them

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had a family history of cardiomyopathy. This highlights the need to perform genetic studies tofurther understand this rare form of cardiomyopathy. [45] In addition, it has been observedthat patients with restrictive physiology have phenotypes for HCM and RCM overlapped inpediatric populations [45].At present it is known that some patients with sarcomeric genetic mutations developRCM [10-16] and that those mutations can produce different phenotypes even within onesingle family. Up to date, RCM has been associated with mutations in genes that codify fortroponin I, troponin T myosin heavy chain and actin. [17-19] Several mutations within thedesmin gene have also been associated with RCM. [20-22] However, the phenotype generallyimplies skeletal myopathy and conduction abnormalities. The new technologies have led to abetter understanding of the genome and the identification of novel mutations that can causeRCM in childhood. The technological advances, such as the ICDs [42], ventricular assistance[49]and transplant have improved the therapeutic options and survival [44-46].In our sample population, 3 patients received the Berlin Heart and were transplantedsuccessfully. Nevertheless, there is not enough information to define when is timely to enrollpatients for transplantation. Furthermore, the outcome of transplant has improved gradually,with a mean graft survival of 12 years or even greater (17 years) for children, exceeding thesurvival rate of the natural history of the disease [45].Some asymptomatic patients pose especial challenges to the physician as to whichtherapy mode to use, since the risk of sudden death is real. Walsh et al. described anomaliesof the conduction system that are produced in this patient population. Bradyarrhythmia andthe development of sudden heart block may be the trigger for events of sudden death. Thesudden death rate reported due to these events is 25% [8] in RCM in children [42].Histopathological evidence for ischemia was found in most patients that died and Holtermonitoring showed that ischemia predicted death. [5] Rivenes et al. [32] described thatsudden death was due to lethal ventricular arrhythmia and showed examples of ventriculartachycardia/fibrillation associated to ischemia. Walsh et al. [41] also described that ischemiawas associated to the appearance of AV block. It is worth noting that those patients with along PR interval are bound to develop AV block, while those with a short PR interval tend toremain unchanged. Another potential disease mechanism of the conduction system could berelated to the atrial and ventricular dilatation as a consequence of the progression of thedisease. Moreover, many of these patients have structurally abnormal myocytes withabnormal gap unions that are believed to lead to the development of abnormalities [29].Patients with long PR interval, wide QRS and left bundle branch block (LBBB) must bemonitored and taken into account to receive ICD/pacemaker [42].Other studies have analyzed the risk to stratify survival up to 8-12 years. [8-10] Otherrisk factors have been identified, such as cardiomegaly, young age, thromboembolic events,pulmonary vascular resistance, pulmonary venous congestion, syncope, chest pain. [26-28]Webber et al. found that the right and left ventricle, the diastolic pressure and the relationshipLA/AO root during presentation of the disease have a negative correlation with the time ofsurvival after diagnosis [51].Up to date, no risk factors that can help detect risk populations in asymptomatic patientshave been identified.

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ConclusionRestrictive cardiomyopathy in childhood is a rare entity with a poor prognosis and a highmortality rate. Of all the cardiomyopathies, RCM has been the most difficult to define, in partdue to poorly defined criteria to categorize this entity.Prospective large pediatric studies are needed to better understand the outcome of thesepatients and risk stratification for sudden death, congestive heart failure, pulmonarythromboembolism and increased pulmonary vascular resistance.Identification of specific genetic mutations will help to better understand the molecularpathology of restrictive cardiomyopathy and create new therapies to delay or reduce thenumber of cardiac transplants.

AbstractTRANSCATHETER CLOSURE OF ASDs- PFOs: The type, size, and shape ofatrial septal defects (ASDs) can vary greatly. Ostium secundum (OS) are the mostcommon ASDs, are present in the region of the fossa ovalis, and account for 75% of allASDs. The position and size of the ASDs, number of defects, distance between thedefects, type of defects, and relationship with other structures must be determined toresult in a successful procedure. ASDs that are not suitable for trans-catheter deviceclosure are sinus venous defects (4-11%) and ostium primum ASDs (15-20%).TRANSCATHETER CLOSURE OF VENTRICULAR SEPTAL DEFECTS (VSD):Common congenital heart disease (20%). Indications for VSD closure are: symptoms ofheart failure; signs of volume overload in left heart chambers; history of endocarditis; andpost-operatory residual VSD with volume overload. The procedure is not recommendedin absence of the crista since this type of VSD has a deficient aortic and pulmonarymargin. The risk factors for complications are age (<5 months) and weight (<5 kg),which are associated with a higher risk of early complications. The localization of thedefect: pmVSD has an increased risk of complete cAVB after device implantation. Thesuccess rate was very high, as closure was successfully achieved in 95.3% of subjects inthe follow-up.AORTIC COARCTATION: Occurs in about 0.04% of live births and comprisesabout 7% of known congenital heart disease. Surgery is the best option in nativecoarctation in patients <25 kg and covered stent in patients >45 years old, to avoid*

E-mail: ana.dedios@gmail.com.

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Ana M.S. de Dios, Jesus Damsky Barbosa, Maria Fernanda Biancolini et al.morbidity. In postsurgical residual gradient, the best option is angioplasty or stent,depending on age, type of defect, elasticity of the wall and other complications. If theaorta must be expanded to adult size, or when the initial measure requires a final diameter3 times greater, covered stent is preferred.Conclusion: Therapeutic intervention helps in congenital heart disease by solving anincreasing number of pathologies and is complementary to other surgical lesions.

Transcatheter Closure of ASDs- PFOs

Atrial septal defects (ASD) are congenital cardiac defects that allow communicationbetween the left and right atria and account for 10% of all congenital heart diseases (CHD).There are several different types of atrial septal defects. Ostium secundum (OS) are the mostcommon ASDs 1, are present in the region of the fossa ovalis and account for 75% of allASDs. They are due to deficiency in the septum primum or, rarely, to an unguardedforamen ovale from deficiency in the septum secundum. In the majority of the defects there isa complete absence, deficiency, or multiple fenestration of the septum primum. The type,size, and shape of the ASD can vary greatly. It is important to note that all these defectsinvolve the fossa ovalis and do not include the vena cava, right pulmonary veins, or atrioventricular valves. The relationships to these structures should be recognized by echo whenconsidering device closure. In the case of ASDs associated with an unroofed coronary sinus,there are publications where the authors describe closure with an Amplatzer device. However,there is no consensus on the best choice for closure of this defect. 2

EchocardiographyTransthoracic echocardiography (TTE) is the primary diagnostic imaging modality forthe diagnosis and description of ASD in children, but the most valuable information can beobtained from transesophageal echocardiography (TEE), especially in adult patients.Rims required:1. 7 mm around the defect for devices > 10 mm2. 5 mm around the defect for devices < 10 mm3. Aortic rim > 3 mmSpecial considerations (Figure 1): The anatomic rims viewed from the right atria surfaceare:1.2.3.4.

The posterior-superior rim: the distance to the superior vena cava.

The anterior-superior rim: the distance to the aorta (Ao).The posterior-inferior rim: the distance to the inferior vena cava (IVC).The inferior rim: the distance to the tricuspid valve (TV) on the right and the mitralvalve (MV) on the left atrium.5. Other nearby structures important to avoid when closing with a device include: thecoronary sinus (SC) and the right pulmonary veins (RPV), the left venous valve of

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the inferior vena cava, and the Eustachian valve, since in some cases this can bemistaken for the inferior rim of an ASD.The information required to close an ASD with a device are: Size of the ASD in mm infour chamber, short axis, and cava axis views using TTE. (Figure 1)

Figure 1. The anatomic rims viewed in a schematic drawing:

Reference:A- The coronary sinus (SC).B- The posterior and inferior rim: distance to the inferior vena cava (IVC).C- The posterior rim: distance to the right pulmonary veins (RVP).D- The posterior and superior rim: distance to the superior vena cava (SCV).E- The anterior and superior rim: the distance to the aorta (Ao).F- The tricuspid valves (TV) on the right and the mitral valve (MV) on the left.

The TEE angle to follow ASD closure is 40-60 in the medium esophagus. This offersthe best view for balloon sizing and the position of the device during the procedure.TEE allows the measurement of the distance to the atrioventricular valves in 0 and thedistance between the defect and the top of the atrium; 35-40 is the best view to show theaortic rim; and 110-120 in the cava axis shows the distance between the defect and thesuperior and inferior vena cava. (Figure 2)The following parameters should be assessed (2):

Presence, type and number of defect/s by TTE and TEE.

Exact defect size determined in at least two planes; the largest measure should betaken into account.Distance from the defect rims to other structures by TEE (atrioventricular valves,coronary sinus, superior and inferior vena cava, aorta, and pulmonary veins).

Quality of the margin defects (rims) by TEE 3.

Entry of the pulmonary veins into the left atria, to rule out anomalous venous return.Right ventricular size, its function, and signs of volume overload (paradoxicalmovement of the ventricular septum).Magnitude of the left to right shunts using non-invasive calculation of the pulmonaryto systemic blood flow ratio (Qp/Qs).Pulmonary artery pressure derived from non-invasive calculation of the rightventricular systolic pressure in the presence of tricuspid regurgitation with nopulmonary stenosis.-Any other associated congenital anomalies, including another ASD, pulmonarystenosis, VSD, etc.Size and systolic and diastolic function of the left ventricle.Mitral valve prolapse and magnitude of mitral regurgitation.

TEE helps to carry out the procedure in 4 basic times: (Figure 3)

First: to recognize localization and extension of the defect.

Second: to measure the ASD by balloon sizing.Third: to recognize residual shunts and to stabilize the device.Fourth: to decide when to release the device.

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Figure 3. The four steps during the hemodynamic procedure. A: First: to recognize localization andextension of the defect. B: Second: to measure the ASD by balloon sizing. C: Third: to stabilize thedevice. D: Fourth: release of the device.

The most important points that should be considered during echo evaluation of ASD are:

The location and size of the ASD, number of defects, distance between the defects,type of defect, and relationship with other structures. (Figure 4)It is necessary to evaluate how to close the defects: with one or two devices.Generally, if the defects are in close proximity, it is possible to close both of themwith only one device. (Figure 5)

Figure 4. Two ASDs near each other (arrows).

Figure 5. Both ASDs closed with only one device.

Figure 6. 3D echo: ASD closed with a Cardias device.

Post-procedure control should be done within 24 hours, after the 1st month, and then 6months later (Figure 6). Antiplatelet therapy is required for six months following theprocedure.Complications: Device migration; device malposition; cardiac erosion/perforationleading to cardiac tamponade and death; atrioventricular heart block; and the usualcomplications encountered in a cardiac catheterization, including air embolism, thrombusformation, infection and hematomas. Thrombus formation is a rare complication, as theprocedure is done under Heparin therapy (100UI/kg). However, as the devices are positionedinto the heart through a delivery sheath (Cook or AGA), this can sometimes producethrombus, generally near the valve, which can be delivered into circulation. (Figure7)

Figure 7. Complication during the procedure: thrombus (green arrow) inside the right atrium.

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When embolization of the device occurs (0.8%), it may be retrieved and used to continueclosing the ASD in the same procedure. (Figure 8)

Figure 8. Device embolization and migration of the device into the pulmonary artery (on the left).The device was recovered and taken inside the right ventricle (on the right).

ASDs Not Suitable for Device Closure

Sinus venous defects (4-11%) and ostium primum (15-20%) are ASDs that are notsuitable for trans-catheter device closure. For coronary sinus defects (<1%), we continue torecommend surgical treatment. Atrioventricular septal defects are contraindicated for transcatheter device closure.Partial or total anomalous venous return, insufficient rims, weight <10 kg, and deviationof septum primum are also situations where it is not possible to close the ASD with a device.Another problem might be not continent or weak ASD walls.The size limit for device closure in ASDs is > 38mm, and in the aortic rim < 3 mm.

Patent Foramen Ovale (PFO)

PFO is a gap between the septum secundum, which forms the limbos of the fossa ovalis,and the septum primum, which forms the flap valve that covers the fossa ovalis. 4, 5, 6, 7The PFO is circular to elliptical in shape and is located in the anterior-superior portion of theatrial septum. The size ranges from 1 to 19 mm, with a mean of 4.9 mm. 8 PFO length alsoreferred to as tunnel length, ranges from 3 to 18 mm, with a mean of 8 mm. 9 Both thediameter and length increase with age. The effective size of the foramen ovale depends on thesize of the space between the two septal components and the degree of valve competency.10. This valve competency can have 3 different situations: stretching of the superior limbosof the fossa ovalis (seen in atrial dilatation) with lack of apposition with the valve of fossaovalis; aneurysm formation of the septum primum that prevents complete closure of atrialcommunication; or real deficiencies of septum primum resulting in a true ostium secundumASD. PFO has become a subject of increasing interest in modern cardiovascular disease. Thishas been the result of several factors including, among others, description of paradoxicalembolism, documentation of PFO with right to left shunt, the rather ubiquitous use of

Trans-cranial Doppler of the vertebro-basilar artery or the right middle cerebral arterywith Valsalva maneuver aids in the clinical diagnosis of paradox reversal shunts 12. Thepresence of 1 to 10 micro bubbles (MB) in the left atrium means minimal shunt, 11 to 25 MBmeans moderate shunt, and more than 25 MB means massive shunt.Another procedure that proves the presence of reversal shunt is using intravenousshacked saline solution. (Figure 9-10)Aneurysm of the atria septum (AAS): in this defect the valve of the fossa ovalis flapsmore than 10 mm around the virtual line of the septum. (Figure11) It is associated with multifenestration of this lamina (2.5%), with no restrictive left to right shunt.

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Figure 11. A: AAS. B: Device closure.

PFO is present in 14.9% to 30% of the population. 13 The combination of PFO andaneurysm of the atria septum is associated with recurrent stroke in 15.2%. However, therecurrence of the stroke without AAS is only 4%. 14Indications for PFO closure are:

-Recurrent stroke associated with the presence of a PFO and reversal shunt inpatients under correct antiplatelet therapy.-Patients that had a stroke and have an AAS.-Patients with atrial fibrillation.-Patients with multi-fenestrated PFO and signs of volume overload.

Trans-Catheter Closure of Congenital Ventricular Septal Defects (VSD)

Ventricular septal defects (VSDs) are a common congenital heart disease (approximately20%). 15. According to their location within the septum, the defects can be classified as:muscular, perimembranous, and supracrystal. 161. The most common are the perimembranous (Pm) VSD (around 70%), whilecompletely muscular VSD may occur in approximately 15% of the cases.2. Supracrystal defects are quite rare, accounting for 5% of all VSDs.3. Rarely, multiple VSDs may be present in a single patient (the so-called Swiss cheeseVSDs).Indications for VSD closure are: symptoms of heart failure, signs of volume overload ofleft heart chambers, history of endocarditis, and post-operatory residual ventricular septaldefect 17 with volume overload. In patients with volume overload of left heart chambers,closure is necessary in order to prevent pulmonary arterial hypertension, ventriculardysfunction, arrhythmias, and aortic regurgitation.

Therapeutic Intervention in Congenital Heart Disease

The anatomic types of VSD are muscular, perimembranous, multiple, or residual postsurgery. The defect must first be measured (Figure 13), and then the number of defectsdetermined as well as their proximity to each other.1. The sub-aortic rim (distance between the defect and the Ao valve) 3 mm or more arerequired in patients with perimembranous VSD (figure 14). Figure 14 B; type ofclosure mechanism (size and morphology). Other structures nearby to recognize arethe mitral (MV) and tricuspid valve (TV) relationship with the defect.2. Associated anomalies in: TV, MV, and Ao regurgitation.3. Procedure details (vascular access, sheath size, pulmonary pressure, Qp/Qs, VSDsize by angiography, type and size of device implanted, associated procedures,residual shunting, fluoroscopic and procedural times).4. Trans-catheter closure of VSDs is achieved by implantation of the device into thedefect, but in Pm VSDs the device is positioned inside of the closure mechanismwhen is necessary.

Figure14. Pm VSD sizing (A) and closure (B). A: Shows the closure mechanism of the Pm VSD byTTE, its size and morphology: orifice on the right and left ventricle and the total length. B: TEE: showsthe distance between the device and the Aortic valve.

ComplicationsA major complication is defined as an event that results in death, long-term sequelae,requires immediate surgery, potentially life-threatening events, persistent arrhythmias needinglong-term therapy (>6 months) or pacemaker placement, ongoing hemolysis requiring bloodtransfusion, thrombosis that requires thrombolytic therapy, or when increased valveregurgitation requires device removal or drug therapy. A minor complication is defined as anevent that requires drug therapy but is not life- threatening and has no long-term sequelae (<6months), or when it does not require long-term therapy. The following are also included inthis group: device embolization with trans-catheter retrieval, hematomas of the groin, cardiacarrhythmias that require cardioversion with drug therapy during the procedure, minor degreeatrio-ventricular blocks, and transient loss of peripheral pulse needing only Heparin therapy.The procedure is successful when the device implantation is in the appropriate positionand when there are no new reasons for surgery (for example, due to significant residual shuntor significant valve regurgitation).

Residual shunt is identified by color-Doppler flow mapping showing a left to right shuntacross the ventricular septum. It is classified as: trivial (<1mm color jet width), small (12mm color jet width), moderate (24 mm color jet width), or large (>4 mm color jet width).Post-procedure complete AV block (cAVB): This can be transitory or definitive. WhencAVB appears during the procedure, we prefer to remove the device to restore sinus rhythm.The procedure should be stopped and the closure programmed by surgery; the risk of cAVBafter the device implantation in pmVSD is high. In our study cAVB was the most significantcomplication and required pacemaker implantation. 26 If this occurs after the procedure, werecommend corticoids to avoid definitive cAVB. In the literature, cAVBs needing pacemakerimplantation are reported to occur in 08% of subjects. This complication is related to theproximity of the conduction system to the margins of the pm VSD. Therefore, both surgeryand device implantation may interfere with atrio-ventricular conduction. Various mechanismsmay be considered as causative. It is possible that the presence of the device may disturbatrio-ventricular conduction by direct traumatic compression. Furthermore, the device mayraise an inflammatory reaction or scar formation in the conduction tissue. However, there isno specific data concerning the mechanisms involved in the occurrence of cAVB afterpercutaneous closure of a pm VSD. Larger studies are needed to clarify the real impact ofarrhythmic problems in these patients and the mechanism of the events. Another dangerouscomplication is the rupture of the tricuspid valve chordae tendineae. 27Atrio-ventricular residual regurgitation with mild repercussion and non-significantresidual shunt may be present after the procedure.In our experience, total occlusion was obtained in 47% of patients at the end of theprocedure, rising to 84% at discharge and 99% during the follow-up. The analysis of riskfactors for complications showed that age and weight were associated with a higher risk ofearly complications. Residual shunt was trivial in 15% and mild in 2% of the subjects.Success rate was very high, as closure was successfully achieved in 95.3% of patients in thefollow-up. This is in agreement with the data reported in the literature, where the success rateranges between 87 and 100% of cases. Trans-catheter closure of congenital VSD offersencouraging results. More experience and long-term follow-up are mandatory to assess itssafety and effectiveness.

Aortic Coarctation (Ao Co)

Coarctation of the aorta is typically a discrete stenosis of the proximal thoracic aorta. Theapparent anatomic simplicity is misleading; however, coarctation varies considerably in itsanatomy, physiology, clinical presentation, treatment options and outcomes. Thepathophysiology of coarctation varies with the severity of the stenosis and is also affected bythe presence of associated lesions, such as patent ductus arteriosus, ventricular septal defectand aortic or mitral stenosis. 28. Coarctation of the aorta is a common form of congenitalheart disease, accounting for 6 to 8% of all cardiac defects. The prevalence of coarctation isincreased in certain disorders, such as Turner syndrome. 29 The most common associatedcardiac anomaly is bicuspid aortic valve, which is present in 30 to 40% of all cases. The mostimportant non-cardiac associated anomaly is intra-cerebral aneurysm (berry aneurysm),present in 10% of all cases.

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Coarctation of the aorta (Ao Co) occurs in about 0.04% of live births and comprisesabout 7% of all known congenital heart disease (CHD). The reported natural history ofuntreated coarctation is poor. The mean age of death for patients with coarctation survivingthe 1st year of life is 34 years (control: 72 years). 30The usual location of coarctation is juxtaductal, just distal to the left subclavian artery;less often, the coarctation is proximal to the origin of the left subclavian artery. The aorticcoarctation may be a long-segment stenosis, and\or may be associated with hypoplasia of thetransverse aortic arch. The abdominal presentation of the aortic coarctation is possible butfortunately is rare. When the location is abdominal, the coarctation can be associated withaortopathies with renal artery stenosis, such as Takayasu syndrome. 31In a collaborative work in 2007, Thomas J. Forbes et al. defined the coarctation of theaorta as the presence of systemic hypertension with an upper to lower limb systolic bloodpressure difference of 20 mmHg or an upper to lower extremity blood pressure differential of<20 mmHg in the presence of systemic hypertension or left ventricular hypertrophy, andconrmation of the coarctation should be done by computerized tomography (CT) scan,magnetic resonance imaging, or echocardiographic assessment. 32Discrete coarctation was dened as a coarctation segment measuring 5 mm. Extensivecoarctation is present when it involves a long segment of coarctation measuring >5 mm.Forbes et al. add that when the obstruction occurred at the level of the transverse aortic arch,the ratio of the diameter of the narrowed segment to the diameter of the descending aorta atthe level of the diaphragm of less than 0.6 was used to dene coarctation in the presence ofclinical evidence of coarctation.Regarding the severity of the aortic coarctation, the Argentine Society of Cardiology(ASC) consensus of 2011 33 based its definition on the systolic arm-to-leg blood pressuregradient: <20 mm Hg: mild Ao Co. 20-40 mm Hg: moderate Ao Co. 40 mm Hg: severe Ao Co.Other signs and/or severity criteria were: hypertension during exercise, heart failureand/or severe left ventricular (LV) dysfunction.

DiagnosisTransthoracic echocardiography confirms the diagnosis. Other imaging modalities(CT/MRI angiograms, cardiac catheterization) may not be obtained routinely unless thediagnosis is in doubt or additional information is needed to plan a surgical or catheterintervention; however, the information obtained by these studies will likely impact our longterm understanding of coarctation repair outcome. Noninvasive MRI/MRA and CTangiography provide a comprehensive view of the thoracic aorta, including the arch,coarctation site, and associated collateral vessels. MRI/MRA is particularly valuable in thefollow-up of patients and permits monitoring of coarctation outcome.

Endovascular TreatmentBalloon AngioplastyAfter experimental trials, percutaneous balloon angioplasty (BA) was established in 1982as a treatment option both for native and recurrent postoperative aortic coarctation. 34-35The incidence of early and late aneurysms after balloon angioplasty has been reported tobe between 5 and 11.5%. 36-37 Increasing age has been found to be a risk factor for asuboptimal outcome. 38 This has been attributed to the presence of fibrotic changes in theaorta secondary to long-standing obstruction 39 and to cystic medial necrosis observed afterpercutaneous balloon angioplasty of Ao Co, with both as potential factors contributing toadverse consequences, such as re-coarctation (RE-CO) of the aorta and aneurysms.In 2003, the Task Force published 40 that BA of native aortic disease can often beachieved with excellent results, although failure to relieve stenosis (1020%), aneurysmformation (510%) and restenosis (510%) have all been reported. BA of previous patchaortoplasty carries the highest risk of aortic rupture and should be performed with surgicalstandby.In 2012, the American Heart Association published 41 that BA for native coarctationcan also be performed safely and successfully beyond the neonatal period. Young patients (>1month but <6 months of age) with discrete narrowing and no evidence of arch hypoplasiamay benefit from BA.This criterion applies to relatively few patients in this age group, because arch hypoplasiacommonly accompanies coarctation of the aorta. However, the recurrence rate is higher foryounger patients (<6 months of age), and there is a small but important incidence ofaneurysm formation after balloon dilation of native coarctation at any age.Our experience covered the years from 1984 to 2005, when we carried out 47 BA inpatients (p) with Ao Co. The mean age was 8 years old 8 months (20 days-19 years old).The procedure was effective in 81% of the cases, reducing the gradient from X: 5017 mmHgto 1410mmHg; 19% had no reduction in gradient.Postsurgical: 17p (13.3%) (Figure: 1-4). 1p died due to a dissection of the aorta (patchaortoplasty with PTFE).Native: 30p (86.7%): 21p with heart failure (HF), 3p with cardiomyopathy and 6pwithout collateral circulation. 1p died during the procedure: a newborn with heart failure(HF).Follow up: re-coartation (67%) and sacular aneurysms (4.2%) (Figure 19). Due to thesecomplications, since 2005 we have indicated BA only in:1. Patients over 18 kg with a localized coarctation of the aorta.2. Patients under 18 kg without collateral circulation.3. Postsurgical re-coarctation. (Figure 18)

Therapeutic Intervention in Congenital Heart Disease

Newborn with Ao Co and heart failure or cardiomyopathy with contraindications for

surgery (palliative).

Figure19. Sacular aneurysm after BA.

Angioplasty with Stent

Since 1980, stent implantation has evolved as an important therapeutic strategy forcoarctation of the aorta. It provides the potential for long-term repair with less chance ofcoarctation recurrence or aneurysm formation. Of course, long-term benefit has yet to beproven. Stents provide a homogenous framework for smooth endothelial growth along theaortic wall that reduces the risk of thrombosis, neo-intimal hyperplasia and subsequentrestenosis. 42. However, at an early age, restenosis by intimal growth may develop. Inaddition, while the incidence of aneurysm formation is low (7%), it is not eliminated by theuse of stents compared to balloon angioplasty alone. 43 Stent implantation for nativecoarctation or re-coarctation of the aorta has also emerged as a beneficial therapeutic optionfor patients who can receive a stent that can be expanded to an adult size. The morbidity

associated with stent implantation for coarctation of the aorta is lower than with surgery orballoon dilation alone. 44 Our experience began with the Palmaz stent in 1993. Before 2000we were using the Cheatam-Platinum (CP) stent (NuMED, Hopkinton, NY) and, after 2002,the CP covered stent (PTFE). The measurements obtained from the angiography were: (1)diameter and length of the stenotic area; (2) diameter of the descending aorta at the level ofthe diaphragm; (3) diameter of the aorta at the level of the subclavian artery; and (4) diameterof the transverse arch.

Experience with Palmaz Stent

In our experience with 35 cases, aged between 6 to 38 years old, the results wereacceptable. The complications that we experienced were:

Experience with CP stent

Bare stent1. Native coarctation of aorta, weight permitted: > 25 kg2. Mild native aortic coarctation with exaggerated hypertensive response to stress3. Postsurgical re-coarctation with recoilCovered Stent1. If the relationship between the initial diameter and the required final diameter isgreater than 3, the best option is to employ the covered stent due to the risk ofdamaging the aortic artery. (Figures 20, 21 and 22)Picture 20- 21-22: Severe aortic coarctation.

Lateral view 1st covered stent. Red arrow:

Lateral view 1st covered stent.

Lateral view 2nd covered stent.

Figure 25. Severe aortic coarctation.

Figure 26. Severe aortic coarctation.

Figure 27. Coarctation of the

aorta with isthmus hypoplasiaand post- Operatory. aneurysm.

Figure 28. Coarctation of the

aorta intra procedure showinganeurysm

Figure 29. Coarctation of

the aorta treated with 3covered stents.

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Ana M.S. de Dios, Jesus Damsky Barbosa, Maria Fernanda Biancolini et al.3. In patients > 45 years old, to avoid bleeding and other major complications.4. What should we consider in a patient with coarctation of the aorta?1. Age and weight: surgery is the best option in patients <25 Kg, and coveredstent in patients >45 years old, to avoid morbidity.2. Native or postsurgical: in postsurgical patients the best solution is catheterangioplasty with or without stent, depending on the age, type of defect,elasticity of the wall and other complications.3. Severity: When it is necessary to expand the aorta to adult size, or when theinitial diameter is less than 3 times the required final diameter, the coveredstent is preferred.4. Localized or extensive membranous type, or tubular type even with hypoplasiaof the isthmus.5. Re-coarctation after balloon angioplasty or stent.6. Compromise of any of the neck vessels.7. Acquired interruption.8. Presence of native or postsurgical aneurysm.9. Indemnity of femoral arteries (history of other procedures).

AbstractEvolving surgical and catheter-based techniques and a collaboration environmentbetween surgeons and interventionalists resulted in the advent of the so-called hybridprocedures in congenital heart disease. Although the hybrid approach starts with acollaborative effort between surgeons and interventionalists, it continues with carefulplanning among different subspecialties such as imaging, intensive care and anesthesia.The goals of hybrid therapies include reduction of morbidity and mortality in patientswith more complex diseases, mitigation of the negative cumulative effects of multipleprocedures, improvement in quality of life and delivery of a more cost-efficient care.Also the hybrid environment encourages the sharing of expertise, ideas, equipment andtechniques, which is crucial to introduce novel therapies for challenging patients. Theseprocedures have significantly expanded the therapeutic options for several patients with*

Alejandro R. Peirone and Carlos A. C. Pedra

complex congenital heart disease in the last 10 years. In this chapter we will discuss theapplication of the hybrid approach in the management of hypoplastic left heart syndrome,muscular ventricular septal defects and pulmonary artery stenosis.

IntroductionSurgical and catheter-based interventions for congenital heart disease (CHD) haveevolved remarkably over the past 50 years. Corrective surgery for intracardiac defects wasintroduced in the 1950s with the advent of cardiopulmonary bypass (CPB). Since then,surgical techniques have been refined progressively resulting in complete repair of morecomplex defects in infants, neonates and even in low-birth-weight premies. Transcathteterprocedures have also evolved, mainly in the 1980s and 1990s, allowing the treatment of avariety of lesions without the use of CPB. In the 2000s, an increasingly collaborativeenvironment between interventional cardiologists and cardiothoracic surgeons led to thedevelopment of the so-called hybrid procedures [1], in which the combined expertise ofboth professionals specialists is used to deliver optimal quality of care and achieve betteroutcomes. The goals of hybrid therapies include reduction of morbidity and mortality inpatients with more complex diseases such as Hypoplastic Left Heart Syndrome (HLHS) andMuscular Ventricular Septal Defects (MVSD), mitigation of the negative cumulative effectsof multiple procedures, improvement in quality of life and delivery of a more cost-efficientcare. Also the hybrid environment encourages the sharing of ideas, equipment and techniques,which is crucial to introduce novel therapies for challenging patients. Although the hybridapproach starts with a collaborative effort between surgeons and interventionalists, itcontinues with careful planning among other subspecialties such as imaging, intensive care,anesthesia and others. These procedures have undoubtedly expanded the therapeutic optionsfor many patients with more complex CHD. This new therapeutic modality has been rapidlygrowing as recently reported by the C3PO registry [2].In this chapter we will review the indications, techniques and outcomes of some commonforms of hybrid therapies such as palliation of HLHS [3], perventricular closure of MVSD [4]and intraoperative stent placement for pulmonary artery stenosis [5].

Hypoplastic Left Heart Syndrome (HLHS)

HLHS is a relatively common cardiac malformation, accounting for 4-9% of all childrenborn with CHD. Since 1981, the Norwood operation and its variants have been considered thegold-standard approach for the treatment of this disease. Despite remarkable improvements insurgical techniques and post-operative care, the overall short and long-term outcomes haveremained disappointing in the majority of centers. Cumulative attrition is the rule with anestimated 5-year survival of only 54% [6]. The classic Norwood procedure with placement ofa modified Blalock-Taussig (MBT) shunt results in a delicate circulation in which balancingthe systemic and pulmonary blood flow may be challenging. Diastolic runoff associated withincreased flow through the shunt and resultant "coronary steal" may increase the risks of thisoperation [7]. To overcome these limitations, a modification of the classic operation wasproposed by Dr Sano and co-workers in Japan [8]. In the Norwood-Sano operation a right

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ventriclepulmonary artery (RV-PA) shunt in lieu of the MBT shunt to provide sufficientpulmonary flow. This technical modification has minimal effects in systemic blood pressureand coronary perfusion, which may potentially lead to a lower perioperative and interstagemortality [8]. In this regard, a recent randomized multicenter study comparing both types ofsurgical approaches showed that the classic Norwood procedure with a MBT shunt hadoverall higher short and long-term morbidity and mortality rates [9]. The transplantation-freesurvival at 12 months of follow up was 64% and 74% for the classic Norwood and the Sanovariation, respectively [9]. Also, a significant incidence of neurodevelopmental disabilitiesand low motor scores has been commonly reported during follow up [10]. All the abovelimitations led to the exploration of other alternatives for the palliation of this challengingdisease.Although ductal stenting and banding the pulmonary arteries (PAs) was first reported inthe UK for initial palliation of HLHS [11], the Giessen group in Germany perfected theprocedure with excellent short and long-term outcomes, comparing favorably with thoseobserved after the Norwood operation [12]. This strategy was popularized by the group fromColumbus, Ohio, USA under the leadership of Drs. Cheatham and Galantowicz [13].Thisstrategy is reproducible and was subsequently employed at other centers [14, 15].In institutions with extensive experience with the Norwood operation, the application ofthe hybrid approach to HLHS is still limited to high-risk neonates for a standard Norwoodoperation and prolonged CPB (i.e.: prematures and/or with other associated conditions). Moreoften, the hybrid approach has been applied for most patients with HLHS irrespective of thepresence of additional risk factors. It shifts the risks of a major operation with the need ofCPB from the neonatal to a later period when the infant is more mature [13]. Despite theincreasing use of this approach, data on long-term outcomes is still limited.The stage I hybrid palliation for HLHS is usually performed in the first days of life andincludes three steps: bilateral PA banding, stent placement in the ductus and balloon atrialseptostomy. In most centers, the initial procedure is performed in a hybrid room via a limitedmedian sternotomy and combines bilateral PA banding and ductal stenting. Prostaglandins areusually discontinued when the neonate is anesthetized. The bands are configured using a 1mm-wide ends cut from a 3.5 mm Gore-Tex tube graft and adjusted in such a way to result ina postductal systemic saturation of 75-80% and a mild increase in the systemic blood pressureof about 10 mmHg [13]. Other techniques such as an adjustable banding system have alsobeen described [16]. After bilateral PA banding, a short 6-7 F sheath is positioned in the mainpulmonary artery (MPA) immediately above the level of the pulmonary valve and secured bya purse string suture. An angiogram is obtained in the lateral view with a hand injectionthrough the side arm of the sheath (Figure 1A). Proper measurements are made with regardsto minimal and maximal ductal diameter and length. The selected stent is advanced over awire through the sheath and should cover the full length of the ductus, between the proximalMPA at the point of the take-off of the right and left PAs and the distal ductal-aortic archjunction (Figure 1B). Incomplete coverage of ductal tissue may result in repeated procedures[17]. Usually stents of 8-10 mm in diameter and 20 mm in length are used in the full termneonate. Occasionally, longer stents or 2 stents in tandem are necessary in a longer duct. Selfexpandable stents are preferred over balloon-expandable stents because they do not interferewith ductal flow and hemodynamics during deployment.This approach is applicable for the initial palliation of most patients with HLHS and alsofor patients with multiple left sided obstructions.

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Figure 1. Ductal stenting in a patient with a Hypoplastic Left Heart Syndrome variant. A: Angiogramtaken in lateral view after bilateral pulmonary artery banding with the sheath secured in the mainpulmonary artery showing a tortuous patent ductus arteriosus with unobstructed right-left shunt. Thebanded left pulmonary artery can also be appreciated in this picture. B: Same view as before afterballoon expandable stent implantation. The length of the stent covered the whole extension of theductus without significant protrusion towards the descending aorta. The stent is well apposed on theductal wall. There is no retrograde aortic arch obstruction.

A relative contraindication of the hybrid procedure in HLHS, especially in those patients

with aortic atresia, is the presence of a severely restricted retroaortic blood flow at the level of

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the distal aortic arch in baseline conditions [13]. Placement of a stent in this setting couldfurther impair the retrograde flow to the aortic arch, neck vessels, ascending aorta andcoronary arteries resulting in acute ischemia and right ventricular dysfuntion. To overcomethis problem and secure adequate coronary flow, an alternative technique was proposed by thegroup in Toronto [18, 19] and consists of placement of a 3-4 mm Goretex shunt between theMPA and the innominate artery at the same time of PA banding and stent insertion.Also, an unrestrictive atrial septal defect (ASD) is required for ideal hemodynamics andprevention of pulmonary hypertension. Typically, a balloon atrial septostomy is performed inthe catheterization laboratory just before hospital discharge. This is performed irrespective ofthe gradient across the ASD and should be considered as an integral part of the hybridapproach for HLHS. The use of new, non-compliant balloons such as the Z 5 (Numed,Canada) has greatly increased procedural success and reduced the need for repeatedinterventions in the interatrial septum. However, in an occasional patient, gradients across theinteratrial septum may increase overtime, requiring additional interventions with alternativetechnique such as static balloon atrial septoplasty (using cutting and standard balloons), radiofrequency perforation and/or stent insertion in the atrial septum [20, 21].The interstage period requires close periodic surveillance. The infant is generallyevaluated every other week with emphasis on weight gain and saturation levels. Arm-legblood pressure and an EKG are also part of the clinical evaluation. Failure to thrive iscommon in infants with HLHS and those with poor growth may be at risk for worse surgicaland neurodevelopmental outcomes. The Feeding Work Group of the National PediatricCardiology Quality Improvement Collaborative has recently published nutrition algorithmsfor infants suffering from this heart lesion [22] and the Columbus group [23] highlighted thatinterstage home monitoring significantly improved weight gain and outcomes in patientsundergoing the hybrid procedure. Potential complications in the interstage period may includeretrograde aortic arch obstruction (RAAO), ASD restriction and ductal stent stenosis and arebest diagnosed using transthoracic echocardiography.RAAO after PDA stenting can be life-threatening especially in patients presenting withthe aortic atresia variant [24]. Careful echocardiographic evaluation should be performedlooking for increasing retrograde gradients across the arch, progressive deterioration in rightventricular function and appearance or worsening of tricuspid regurgitation, which are allassociated with myocardial ischemia and possible new EKG changes. Patients with smalleraortic roots, higher retrograde aortic flow velocities on initial echocardiogram and a moreacute angle between the arch and the ductus on the initial angiogram are at highest risk fordeveloping RAAO [24]. The treatment for this complication is either an earliercomprehensive stage II procedure (when the patient is 3-5 months of age) or retrograde stentplacement through the cells of the previously implanted ductal stent. Recurrent or residualductal stent stenosis is another potential problem that might occur during the interstageperiod. If this complication is observed during the echocardiographic Doppler assessment, itis best managed implanting a second ductal stent [17]. The balloon expandable stent isusually preferred in this setting because the higher radial forces necessary to expand aresidual obstruction. Recurrent ASD obstruction may occur but it has been unusual using thecurrent techniques and materials. Alternative techniques such as those outlined above areused to manage this intersatge complication.The comprehensive stage II palliation is usually performed at 6 months of life when thepatient weighs 5-6 kg [13]. This big operation includes debanding and reconstruction of the

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branch PAs, atrial septectomy, bidirectional Glenn anastomosis, aortic arch reconstructionand incorporation of the small native ascending aorta into the newly created neo-aorta using avariety of techniques. Although most centers advocate complete removal of the ductal stent,the Toronto group suggested a modified arch reconstruction leaving part of the stent as aretained stented ductus patch [25]. Typically these patients behave as post-operative Glennpatients with more stable hemodynamics. Possible complications of this operation includepulmonary artery stenosis and distortions, which may be associated with local thrombusformation. Early diagnosis using exit angiography [26] and aggressive treatment with intraoperative stenting (see below) or in the first days after the operation may be required.Although some have raised some concerns with regards adequate pulmonary arterygrowth after the hybrid strategy for HLHS palliation, Honjo et al [27] from the Hospital ofSick Children in Toronto showed that the hybrid palliation does not have a significant adverseimpact on pulmonary artery development, with similar pulmonary artery growth,hemodynamics, survival and diminished hospital utilization when compared with Norwoodstrategies. Finally, the same group has recently reported their experience comparing hybridversus Norwood strategies for single-ventricle palliation [28]. A longitudinal evaluation wasundertaken since the two strategies differ substantially in terms of the stage II palliativeprocedures. Freedom from death / transplant after stage II palliation was equivalent betweengroups although hybrid patients had a higher pulmonary artery reintervention rate and lowerNakata index at pre-Fontan evaluation. Aortic arch and atrioventricular valve reinterventionswere not different between the groups and the ventricular end-diastolic pressure, meanpulmonary artery pressure, and ventricular function were equivalent. Survival after stage IIpalliation and subsequent Fontan completion was equivalent between both groups.It seems that more and more centers are embracing the hybrid approach for the initialpalliation of neonates born with HLHS. With increasing number of patients and longerfollow-up, a prospective multicenter trial comparing both strategies would be ideally requiredfor proper assessment of outcomes. However, this is unlikely to occur in the real world sincethere is a wide variation of institutional policies and preferences. Also, it should beacknowledged that there are institutions that perform better doing Norwoods and others doingHybrids. Customization and offering the patient what you do best are crucial to achieveoptimal outcomes.

Perventricular Closure of Muscular

Ventricular Septal DefectsMuscular ventricular septal defects (MVSDs) accounts for about 20% of all congenitalventricular septal defects [29]. They can be located in the trabecular, apical or anterior regionof the interventricular septum and are usually distant from the atrioventricular node. When thedefect is restrictive, the natural history usually shows spontaneous closure in most patientswithin the first 4-5 years of life. Treatment is indicated when the defect results in heart failurein infancy or when there is volume overload of the left ventricle on echocardiography [29].Percutaneous closure of such defects was introduced in the late 80s [30] but was fraught withtechnical limitations inherent to the available devices at that time. With evolving devicetechnology and the advent of nitinol devices to close intracardiac defects the results of

Hybrid Procedures for Congenital Heart Disease

that closure of such defects with a nitinol self-expandable double-disc device was feasibleresulting in excellent outcomes in patients from infancy to adulthood [31]. However, itsapplication to the small infant < 5-6 kgs was associated with a higher risk for complicationsincluding hemodynamic compromise, arrhythmias, cardiac perforation, tamponade and death[31]. The concept of intraoperative closure of VSDs via a perventricular approach wasintroduced by Amin and co-workers in the late 90s [32]. In this procedure, after a standardmedian sternotomy is performed by the surgical team, a delivery sheath is advanced throughthe anterior wall of the right ventricle (RV) (Figure 2) across the defect into the left ventricle(LV). Under transesophageal echocardiographic (TEE) guidance, an intracardiac device isimplanted through the delivery sheath by the interventionalist. Initial and subsequentexperiences documented its feasibility, reproducibility, safety and efficacy in this high riskage group [4, 29, 33].Perventricular closure of MVSDs is mainly indicated for the small infant (<6 kgs) withlarge and unrestrictive MVSDs, suffering from intractable heart failure, pulmonaryhypertension and failure to thrive [29]. These patients are too fragile to undergo a longcardiac catheterization procedure in which the need to establish an arterio-venous wire loopresults in hemodynamic compromise. Also vascular issues may be an additional limitingfactor. Small infants with associated lesions that require surgical repair, such as coarctation ofthe aorta, double outlet right ventricle, transposition of great arteries and status-postpulmonary artery banding, may also benefit from the perventricular approach. After deviceclosure of the MVSD, the associated lesion can be surgically repaired at the same session inthe operating room (OR). Avoidance of CPB or limiting its time is a major advantage of theperventricular approach resulting in less morbidity, both in the short and long term, and fasterrecovery.Technically, the procedure is performed under general endotraqueal anesthesia. A mediansternotomy or a limited subxiphoid incision is performed and under continuous TEEguidance, the RV free wall is punctured through a purse string using an 18-gauge needle in alocation that is perpendicular to the plane of the MVSD. Sometimes, a gentle manual orinstrumental RV compression is helpful to determine the ideal location of the puncture. Avariety of wires can be used to cross the VSD but the J-tipped short wire that comes withthe short sheath is the most frequently employed. It is important to measure the distancebetween the RV free wall and the LV posterior wall to avoid injury of the LV posterior wallcaused by sheath and dilator progression (Figure 3). Once the short sheath is properlyvisualized by echocardiography in the LV cavity, the selected self-expandable double-discdevice (with a waist 1-3 mm larger than the largest diameter of the defect measured indiastole by TEE) is advanced. The distal disc is carefully deployed in the free LV cavity(away from the mitral valve apparatus). After minimal deployment of the central waist thewhole system is pulled back as a unit against the interventricular septum until some resistanceis felt. Further retraction of the sheath and advancement of the delivery cable using a twohand technique is required to fully deploy the waist within the defect and the RV disc in theRV (Figure 4). After ruling out any significant AV valve regurgitation or residual shunt, thedevice is released, the short sheath is removed and the purse string is closed. Finally, surgicalclosure of the sternotomy is performed.

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Figure 2. Perventricular device closure of a large muscular ventricular septal defect in a small infant.Sheath positioning across the right ventricular free wall. Left panel: An 8 F Standard short sheath ispositioned through the right ventricular free wall. Note the suture on the sheath abutting the rightventricular wall. Right panel: After the device is transferred from the loader to the short sheath,implantation is performed with gentle movements, pulling on the sheath and pushing on the deliverycable.

ventricular septal defect. Four-chamber view. Left upper panel: Single muscular ventricular septaldefect located in the mid-trabecular area of the sepum measuring 9-10 mm. Right upper panel: Thedistance between the anterior right ventricular free wall and the posterior left ventricular wall ismeasured (35 mm). Left lower panel: Internal bulging of the anterior right ventricular free wall after itis gently pushed using the index finger. Right lower panel: A J-tip 0.038 echogenic guide wire is seenacross the defect into the left ventricle.

Hybrid Procedures for Congenital Heart Disease

upper panel: The short 8 F sheath is seen across the defect. The tip is located in the mid left ventricularcavity, away from the posterior wall. Right upper panel: The left disc and the waist of a 12 mm deviceare deployed in the mid left ventricular cavity. Left lower panel: The left disc is approaching theinterventricular septum. Right lower panel: Adequate device positioning within the septum.

In an occasional patient, the defect cannot be crossed from the RV free wall, especiallywhen it is located below the moderator band in the heavily trabeculated area of theinterventricular septum. In this setting, the creation of an arterio-venous loop followed bywire snaring through the perventricular sheath may facilitate sheath progression through thedefect [34]. In more apical defects, there may not be enough room for complete RV discreconfiguration. In such cases a patent ductus arteriosus device can be used instead and/or thepin of the RV disc sutured in the RV wall to provide optimal stability [29].

Hybrid Approach to Branch Pulmonary

Artery StenosisTreatment of PA stenoses continues to be challenging for patients with a variety oflesions, particularly those with conotruncal anomalies such as tetralogy of Fallot, truncusarteriosus, as well as pulmonary atresia and ventricular septal defects. Surgical patchangioplasty and transcatheter stent therapy are the current treatment options for PA stenoses.

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Generally, surgical patch angioplasty is fraught with vessel distortions and tissue scarringresulting in suboptimal outcomes. The use of endovascular stents for the treatment of suchstenoses, pioneered by Dr. Charles E. Mullins, improved the immediate results and the ratesof restenosis [35]. However, percutaneous delivery of large stents that can be redilated toadult size requires high profile delivery systems, is technically demanding and not withoutcomplications. Due to these drawbacks, the idea of intraoperative delivery of endovascularstents in the operating room emerged as an alternative treatment option to increase the safety,ease and effectiveness of these procedures. The experience with the hybrid intraoperative PAstenting has increased significantly in the recent era, accounting for about 11% of all hybridinterventions [2]. Not every patient and not every lesion are suitable for intraoperative stentplacement, and the choice of the appropriate treatment strategy should be tailored to theindividual patient.The first description of this technique was reported by Mendelsohn et al in 1993 [5] andsince then, many centers have adopted this strategy with reproducible outcomes in terms ofsafety and the efficacy [36, 37]. Hybrid stent delivery is commonly performed in theoperating room under direct or cardioscopic vision with an opened PA under CPB or througha sheath inserted in the PAs or in the right ventricular outflow tract before or after theinitiation of CPB under angiographic guidance (Figure 5). Although this procedure can bedone using a portable fluoroscopic C-arm, a well-equipped hybrid suite should be consideredthe ideal environment to perform such complex interventions (Figure 5).

AFigure 5. (Continued)

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BFigure 5. Intraoperative pulmonary artery stenting in a patient status post Tetralogy of Fallot repair withfree pulmonary insufficiency and bilateral pulmonary artery stenosis. A: After a bioprosthetic valve wasplaced in the pulmonary valve position and the proximal left pulmonary artery was patch repaired, anangiogram performed in the main pulmonary artery after discontinuation of cardiopulmonary bypassshowed significant proximal right pulmonary artery stenosis. The stenosis is related to the position ofthe vessel behind the dilated ascending aorta. Surgical instruments are evident in the picture. B: Stentimplantation through a sheath positioned in the main pulmonary artery resulted in optimal stenosisrelief in an angiogram obtained immediately after implantation. This strategy was planned before thepatient was brought to the operating room and resulted in speedy recovery with hospital discharge in 5days.

The target lesions should be initially assessed using integrated imaging modalities [26]with the use of angiograms of previous caths, magnetic resonance imaging and computedtomography. The optimal delineation of the underlying anatomy beforehand allows to select aproper size stent expediting the procedure, saving time and contrast injections. Also, newsoftware protocols allow beautiful digital imaging fusion in modern hybrid suites.The advantages of hybrid stent delivery include no size restrictions for sheaths, cathetersand stents, avoidance of tortuous courses and better catheter and stent navigation, no need forstiff wires and long sheaths, no interference with tricuspid and pulmonary valve function thatmight cause hemodynamic compromise, possibility of manually cutting the stent to adjust forindividual requirements, shorter procedural time, fluoroscopy time and radiation exposure,and better control of complications such as stent migration, or mal position, balloon ruptureand vascular injuries.

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Figure 6. Exit angiography and intraoperative stent implantation in a patient with univentricular heartand multiple stenosis in the pulmonary arteries. A: Exit angiogram after a Glenn operation and patchenlargement of both pulmonary arteries was performed. Significant stenosis at the origin of bothpulmonary arteries is appreciated in this angiogram performed in right anterior oblique with caudalangulation view. B: Bilateral stent implantation was undertaken through a sheath positioned in thesuperior vena cava. Optimal relief of stenosis was achieved, which resulted in speedy recovery andearly extubation. Because of the presence of surgical instruments, the lesion should be profiled usingvariations of usual projections in the hybrid room.

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The need for sternotomy and/or CPB should not be considered a disadvantage becausethese patients are usually brought to the OR for concomitant intra cardiac surgical repairs.The decision as to whether implant the stents under direct or cardioscopic vision orangiographic guidance on the beating heart depends on the type of surgical procedureperformed, the need for CPB, the availability of a cardioscope, the presence of comorbiditiesthat may increase the risks of contrast induced renal injury and institutional policies. Preexisting landmarks and measurements should be assessed and taken in previous angiographicand imaging studies (if available) no matter what the employed technique is. Fluoroscopicguided stenting is usually applied for patients that require an exit angio to assess immediatesurgical results for whatever reason. Patients with pre-operative abnormal PAs, regardless ofthe underlying disease, who also require repair of associated intra cardiac lesions are commoncandidates for hybrid stent implantation. When there is bilateral central PA stenosis requiringkissing stents, the surgeon can bend the proximal stents struts towards the carina under directvision in order to secure free access in future catheter procedures. Also, dilatation of a stentcell may be performed under direct or cardioscopic vision to secure access to a branch vesselin future cath procedures. Finally, transapical access for hybrid stent delivery is an additionaltechnique that can be used for patients who do not need a median sternotomy for surgicalrepair of associated lesions. A limited subxiphoid incision is performed and a purse stringsuture placed at the right ventricular apex in order to facilitate a more straight progression ofsheaths, catheters and stent. This has been employed in very small patients with vascular sizerestrictions and in those with very tortuous venous course that could preclude percutaneouscatheter progression. Immediate results of intraoperative stent implantation are assessed byserial angios or direct cardioscopic vision. The ability to treat any residual PA lesion beforetransferring the patient to the intensive care unit is crucial for a speedy recovery and better inhospital outcomes (Figure 6).In conclusion, exit angios and hybrid stent delivery to the PAs has changed the landscapeof the treatment options for PA stenosis. The collaboration between surgical andinterventional teams resulted in better outcomes for these challenging patients.

AbstractThe surgical management of transposition of the great arteries with ventricular septaldefect and left ventricle outflow tract obstruction is a true challenge in congenital heartsurgery. Different surgical techniques such as the Rastelli procedure, Reparation a`lEtage ventriculaire, the Metras modification, Nikaidoh operation and its modificationswere defined.Although the Rastelli operation has been the most widely performed surgicalprocedure over the past decades, several studies have shown suboptimal long-termprognosis after its practice. A newer operation described by Bex and Nikaidoh has beenperformed with promising outcomes. The anatomical characteristics usually enablebiventricular repair, though in some hearts univentricular palliation may be the onlysurgical option.

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IntroductionTransposition of the great arteries (TGA) with a ventricular septal defect (VSD) and leftventricular outflow tract obstruction (LVOTO) represents 0.67% of all congenital heartdefects [1]. Although unusual, this lesion remains a surgical challenge.The optimal treatment strategy for these patients is controversial due to high anatomicalvariability and unsatisfying long-term results. The anatomic correction of these lesionsrequires complete reconstruction of the biventricular outflow tract.The arterial switch is contraindicated when pulmonary stenosis (PS) would be convertedto significant aortic stenosis.Three major surgical techniques have been developed during the past three decades: theRastelli procedure, Rparation a l'tage ventriculaire (REV) and the aortic roottranslocation with biventricular outflow tract reconstruction (Nikaidoh procedure).

Surgical Procedures: A Journey towards the Corrective Surgery

Rastelli ProcedureIn 1969 Giancarlo Rastelli of the Mayo Clinic proposed the surgical procedure that bearshis name for the treatment of patients with transposition of the great arteries (TGA) with VSDand LVOTO. [2, 3, 4]

Figure 1. Echocardiographic image of a patient with DORV, subaortic VSD and PS undergoing theRastelli procedure at the age of 3 years and 7 months, who developed severe subaortic stenosis 5 yearsafter surgery. A and B: subaortic stenosis and the left ventricular baffle to the aorta with anterior andright orientation in the left parasternal long axis view. C: gradient of severe subaortic stenosis in a fivechamber apical view.

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This procedure soon became the standard surgical treatment for this pathology and itspractice extended to other congenital heart defects as double outlet right ventricle (DORV)with pulmonary stenosis as well.Rastelli procedure includes an intraventricular rerouting to create a left ventricularoutflow tract by the use of an intracardiac patch that directs the blood from the left ventricle(LV) to the aorta through the VSD. The right ventricular outflow tract is reconstructed andcontinuity between the right ventricle (RV) and the pulmonary artery (PA) is achieved bymeans of an extracardiac valved conduit.This technique has the clear benefit of preserving the function of both ventricles(biventricular repair) with left ventricular baffling to the aorta. [5]The Rastelli operation has been the method of choice over the past four decades. [6]. Theprocedure can be performed with low early mortality. However it is a complex procedurewith marked morbidity and mortality in the medium and long-term follow-up. [7, 8, 9, 10, 11,12]

Figure 2. Interventional catheterization procedure of a patient with DORV, VSD and LVOTO whounderwent Rastelli procedure at the age of 4 years and 8 months. Eight years after surgery he developedsevere stenosis of the homograft. A: stenosis of the homograft in pulmonary artery position. B and C:balloon angioplasty dilatating the stenosis. D: angiography following the successful procedure.

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Figure 3. Angiography of a patient with DORV who underwent systemic-to-pulmonary artery shunt atthe age of 7 months and Rastelli procedure at 3 years and 7 months old. Balloon angioplasty of the rightpulmonary artery and stent implantation in the left pulmonary artery (images) were required 7 monthsafter surgery.

The most frequent complications are residual VSD, development of left ventricularoutflow tract obstruction, stenosis or insufficiency of the right ventricle-pulmonary arteryconduit (RV-PA), ventricular arrhythmias and dysfunction. [13, 14]. Accordingly,reintervention and reoperation rates following the Rastelli procedure were frequently needed.[15]Replacement of the extracardiac conduit is usually required. Extracardiac RV-PAhomografts appear to be less durable than homografts in an orthotopic pulmonary position.[16, 17] Reoperation has been frequently informed for residual or recurrent LVOTO.

Strategy for Biventricular Outflow Tract Reconstruction

We reported our experience with Rastelli repair in 47 patients with a mean follow-up of 6years post-op (15 months-14 years) [8]. Thirty nine reinterventions were performed (1 day 13 years): 12 interventional catheterization procedures in 9 patients and 27 reoperations in 22.The causes of reoperation are shown in Figure 4 and they were more frequent when theVSD was anatomically remote or non-committed to the aorta.Several procedures have been reported as alternative to the Rastelli repair with varyingresults.Reparation a letage ventriculaire (REV)The Reparation a letage ventriculaire described by Lecompte in 1982 [18] entailsresection of the infundibular septum along with reconstruction of the pulmonary outflow tractwithout using a prosthetic conduit by wide mobilization of the pulmonary arteries andreimplantation of the pulmonary trunk to the RV [19]This surgical technique has the potential to decrease the incidence of LVOTO whatpreserves left ventricular function and improves long-term outcome [20]However, the free pulmonary regurgitation following RV outflow reconstruction remainsa concern in the early and the late postoperative period. [21]Nikaidoh ProcedureThe presence of a non-committed or restrictive VSD, a straddling mitral or tricuspidvalve, cone-shaped implants of the tricuspid valve or the anterior implant of the mitral valve,a small right ventricular and/or an unusual coronary anatomy are anatomic variables thatcomplicate the performance of a Rastelli/REV operation. [8, 9, 22, 23, 24, 25, 26, 27, 28, 29,30, 31].Aortic translocation becomes an attractive alternative when anatomy does not allowintraventricular rerouting (Rastelli/REV repair).

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Figure 5. Patient with DORV, right anterior aorta and PS. A) Parasternal view showing mitralsemilunar valve discontinuity (arrow). B) Anatomic view (short axis of ventricles): VSD and bothvessels emerging from the right ventricle (RV) with the aorta (Ao) in the right and anterior side. Thepulmonary artery (PA) is of small size with a stenotic bicuspid valve. Both images show noncommitted VSD.

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Figure 7. Angiography of a patient with DORV type TGV with PS. A) Right ventriculography. B) leftventriculography: both great arteries emerge from the right ventricle. Note the remote VSD.

Figure 8. Patient with TGA, VSD and LVOTO. Transesophageal echocardiography in the operatingroom before surgery. A) Mid esophageal view at 85: the aortic artery (Ao) emerges from the RV. B)Mid esophageal short axis view at 45: relationship between the great arteries and the aorta in the rightand anterior side. C) Mid esophageal long axis view at 120: a stenotic pulmonary artery (PA) emergesfrom the left ventricle (LV).

This new surgical approach for the TGA, VSD and SP denominated aortic translocationand biventricular outflow tract reconstruction was proposed by Hisahi Nikaidoh of theChildrens Medical Center of Dallas in 1984. [32]This repair consists of harvesting the aortic root and attached coronary arteries from theright ventricle and relieving the LVOTO (the outlet septum is divided and the pulmonaryvalve is excised). The left ventricular outflow tract (with the posteriorly translocated aorticroot and the VSD patch) and the right ventricular outflow tract (with a pericardial patch) areboth reconstructed.Nikaidohs original technique described a direct mobilization of the aortic root withoutdetaching the coronary arteries. Several modifications were introduced later: coronarytransfers preventing coronary insufficiency, Lecompte maneuver and homograft interpositionconnecting the RV infundibulum to the pulmonary trunk to improve reconstruction of theright ventricular outflow tract. [21, 23, 30, 33, 34, 35, 36, 37]

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Though technically demanding, the Nikaidoh procedure theoretically has several

advantages: it can be performed early in life avoiding multiple palliations, cavity and volumeof the RV are not reduced, a straight alignment of both outflows is created likely improvingLV and RV function, LV is anatomically connected to the aorta and the RV- PA conduit isorthotopical and the right ventricle is preserved [20, 31]Despite the small number of patients and follow-up data, the Nikaidoh procedure and itsvarious modifications have been performed with promising outcomes.The midterm follow-up for LVOTO has not been reported. Frequent complications are:stenosis or insufficiency of the pulmonary artery or the RV- PA conduit, aortic regurgitation,ventricular arrhythmias and dysfunction. [20, 21, 23, 30, 33, 34, 35, 36, 38, 39, 40]Aortic valve regurgitation which is not progressive and usually appears in the immediatepostoperative period is a matter of concern [30, 40]. An adequate surgical technique of aorticroot transfer avoids this complication.Since 2005 we have been using the Nikaidoh procedure in our hospital with encouragingpreliminary results so far.Nine patients with TGA + VSD + LVOTO and two patients with DORV + SP havealready been operated. The surgery consisted on aortic translocation, reimplantation ofcoronary arteries and right ventricle-to-pulmonary artery connection using homografts. The11 patients had a non-committed VSD and one of them had a mildly hypoplastic RV.

No deaths have occurred after this procedure. After 4.3 years on average (25.6 years)from surgery, all patients are in NYHA functional class I with neither arrhythmias norLVOTO and have normal biventricular function. Only mild aortic insufficiency has beenobserved. There was one reoperation in a patient who developed post-surgery infectiveendocarditis and needed a mitral valve and RV-PA homograft replacement. Another patientunderwent balloon angioplasty of the stenotic homograft RV-PA. Figures 11 and 12respectively show immediate and mid-term surgical results.

Aortic translocation and biventricular outflow tract reconstruction result in a more normalanatomic repair, which could result in improved cardiac performance and long-term survival.The risk of subaortic obstruction is reduced because left ventricular outflow tracts areproperly aligned.The RV-PA conduit originates normally from the right ventricle and is therefore lesssusceptible to sternal compression. It may last for a long time with a decreased incidence ofreoperation. [30, 36].

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In patients with TGA + VSD + LVOTO who are inadequate for an intraventricularrerouting (Rastelli/REV operation) the Nikaidoh procedure arises as the best surgery optiondue to its mid-term results. [23, 31, 34, 40].

AoLA

Figure 13. Echocardiographic image ofa patient with DORV with VSD and PS undergoing the Rastelliprocedure (A) and the Nikaidoh procedure (B). A: notice the wrong alignment between the leftventricular (LV) and the aortic artery (Ao) with an elongated and stenotic baffle. B: notice the properlyaligned LVOTO without obstruction.

Univentricular correction should be considered when surgical repair is not possible. TheVAFontan-Kreutzer procedure might be superior to the high-risk biventricular repair despite theowell-known long-term problems associated with single ventricle circulation. [31]

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ConclusionThe transposition of the great arteries with ventricular septal defect and left ventricularoutflow tract obstruction, regardless of its low prevalence among congenital heart diseases,represents a serious challenge for pediatric cardiac surgeons.The optimal surgical treatment of these patients is controversial.Up to now the Rastelli procedure has been the most frequent surgical treatment eventhough its long-term results are not optimal.In the subgroup of patients with TGA + VSD + LVOTO who are inadequate for anintraventricular rerouting (Rastelli/REV operation), the Nikaidoh procedure emerges as thebest surgery option in terms of the immediate hemodynamic results and the comparativelyfewer complications in the medium and long-term.Although the Nikaidoh operation and its modifications have been performed withpromising outcomes, a larger number of patients and longer follow-ups are required toevaluate the long-term benefits.Finally, univentricular palliation can be the only surgical option in some hearts.

Adult Congenital Heart Disease:

AbstractMajor advances and refinement in the diagnosis and surgical treatment of congenitalheart defect in the last four decades has resulted in an increasing number of adultsurvivors [1, 2].The incidence of congenital heart diseases is around 1%. Nearly 6000 children areborn with one congenital heart defect in Argentina per year [3]. Two thirds of themrequire surgical treatment mostly within the first year of life. Fortunately, surgicalmortality has been reduced to low single figures in the last 20 years and 90% of theoperated patients are expected to reach adulthood. It is noteworthy that congenital heartsurgery is reparative and not curative. Except for the ligated patent ductus arteriosus inthe first months of life, all congenital heart lesions whether operated on or not willrequire lifelong control. Even the Atrial Septal Defect (ASD) operated upon in the firstyears of life may be exposed to the development of atrial fibrillation or sick sinus diseasein the fourth decade.

Population ProfileWe are facing two groups of adult patients with congenital heart disease: those operatedon in infancy or childhood and patients who reached adulthood without diagnosis or surgicaltreatment.

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The operated group makes up a growing population not only in size but also concerningwith the complexity of their heart defects. Most of them are diagnosed and treated in hospitalsor pediatric institutions by the pediatric cardiac team.The untreated patients are those who were not diagnosed in childhood due to the absenceof symptoms or the presence of mild clinical signs that might have been overlooked. In thisregard, the ASD typically accounts for about 30% of congenital heart defects diagnosed inadulthood.There are also certain heart lesions within this group that may have a rather late clinicalmanifestation regardless of their complex morphology. Examples of these are the Ebsteinsdisease or the congenitally corrected transposition of great vessels (atrioventricular andventriculoarterial discordance).The majority of the untreated patients usually attend the cardiology department at publichospitals. We have been collecting data of these adult patients in Garrahan and ArgerichHospitals for the last 25 years and keep a data base of 1520 patients coming from all over thecountry and neighboring countries as well (Figure1).

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Unoperated patients make up 65% of the whole population and received medical care atthe Argerich Hospital or other public hospital for adults (Figure 2). Most of the operatedadults in our database come from the Garrahan Hospital where over 500 patients are operatedyearly with an overall mortality of less than 5%.

Problems and Needs

The most frequent ensuing adverse events are the development of arrhythmias, rightventricular failure, pulmonary hypertension and infective endocarditis. Patients look foradvice on additional special topics such as pregnancy, contraception, genetic transmission,physical exercise, work activity, health and life insurances. Hereafter we will briefly addresssome of the adverse events above mentioned [4].

ArrhythmiasArrhythmias are a very common cause of symptoms and may trigger serioushemodynamic events. They may emerge as part of the natural history of the underlyingdisease or they may be related to the surgical procedure or acquired later during the long-termfollow-up. Arrhythmias usually have an underlying anatomic or hemodynamic substratewhich should be identified and treated [5].Atrial arrhythmias like atrial fibrillation, flutter or re-entrant atrial tachycardia are usuallyassociated with dilation of the right atrium due to chronic volume overload or fibrosissecondary to surgical scars. These may appear late in the follow-up in complex lesions suchas the Fontan-Kreutzer surgery in patients with univentricular physiology, the Senningprocedure in transposition of the great arteries or Ebsteins disease. Nevertheless, they mayoccur also in simple defects like the ASD which is the most frequent congenital heart defectdiagnosed in adulthood [6]. Eighteen percent of the unoperated patients and 2% of theoperated patients had atrial fibrillation at age 55 on average in the follow-up of 350 adultcases with ASD from our database (Figure 3).The most serious and life threatening ventricular arrhythmias are related to surgicalventriculotomies, fibromuscular resections, obstructive outlet tracts or pressure and/or volumeoverload of the right ventricle.The typical case is that of patients with Tetralogy of Fallot after surgery. In ourexperience with 236 adult patients undergoing surgery, 29 years old on average (range 18 yrs64 yrs) and followed over 25 years, ventricular arrhythmias were present in 25% of thepopulation.Most of them had extensive ventriculotomies and pressure and volume overloadassociated to distorted and stenotic pulmonary branch arteries following aortopulmonaryshunts.

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Figure 3. Eighteen percent of the unoperated patients and 2% of the operated patients had atrialfibrillation at age 55 on average in the follow-up of 350 adult cases with ASD from our database.

In surgical patients with Tetralogy of Fallot, the pressure and/or volume overload of theright ventricle associated to large ventriculotomies is the morphologic substrate fordeveloping life threatening ventricular arrhythmias.Likewise, there is an intimate relationship between the electrical disorders secondary toresidual structural defects and the development of right ventricular dysfunction.

Dysfunction of the Right Ventricle

Right ventricular failure is a frequent cause of late morbidity and mortality in patientswith congenital heart disease. This may happen in cases when the right ventricle is normallylocated in the subpulmonary position as it is in Fallots tetralogy. Chronic pulmonaryregurgitation secondary to a transannular patch leads to right ventricular failure in the longrun. Severe pulmonary insufficiency after the third or fourth decades of life is the mostfrequent cause of reoperation in adults with this condition [4, 7].Currently, cardiac magnetic resonance is the gold standard diagnostic modality for theevaluation of volumes and function of the right ventricle. It allows referring confidentlyasymptomatic patients to surgically restore pulmonary competence before heart failureensues.On the other hand, dysfunction of the right ventricle may arise in those pathologies wherethe right ventricle sustains the systemic circulation. The best examples of this situation are thetransposition of the great arteries with a previous physiologic surgical procedure whichinvolves a rerouting of the systemic and pulmonary venous returns (Senning or Mustardprocedures) and the congenitally corrected transposition. The capacity of the right ventricle tofunction as the systemic pump over time has gained growing concern since the beginnings ofcongenital cardiovascular surgery. There is evidence that, in the absence of tricuspidinsufficiency, the right ventricle could function properly up to 20 or 25 years after surgery.

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However, when it is associated to a progressive tricuspid regurgitation, as usually observed in

patients with congenitally corrected transposition, the right ventricular failure appears earlier[8]. In this regard, the arterial switch operation for transposition of the great arteries thatreconnects each large vessel to its corresponding ventricle has become by now the procedureof choice. Likewise, in order to avoid the dysfunction of a systemic right ventricle, there iscurrently a growing tendency to perform a double switch procedure (atrial and arterial) inchildren born with a congenitally corrected transposition [9].

Pulmonary Vascular Disease

It is a serious complication that may occur in either unoperated or operated patients withleft-to-right shunts or late when the pulmonary artery resistances have already increased tosystemic or supra systemic levels and thus, an Eisenmenger syndrome (ES) developsreversing the shunt and the patient turns cyanotic. We have seen 55 patients, aged 18 to 66years (28 yrs on average) in our experience at the Argerich and Garrahan Hospitals. Theypresent multiple and complex problems related to chronic cyanosis and represent a challengeto cardiologists at the time of relevant decisions, such as the indication of phlebotomy,contraception, or heart transplantation [10]. This topic will be covered in depth in theEisenmenger Syndromes chapter in this book.

ConclusionAdult Congenital Heart Disease: An Unprotected CommunityThis special and increasing group of patients should be treated in specialized centers foradult congenital heart disease. These centers could be located in an adult general hospital orin a special center created in a pediatric hospital largely experienced in medical and surgicaltreatment of complex heart lesions and reoperations. Nowadays many pediatric hospitals inUSA treat these adult patients routinely such as is the case of the childrens hospitals inHouston, San Francisco, Boston, etc. In our experience, better surgical results were achievedwhen patients underwent surgery in pediatric hospitals with staff trained for congenitalcardiology. On the other hand, this community is not a priority for adult cardiovascularsurgeons who have been rarely exposed and much less trained in congenital heart defects andare highly demanded by coronary or valvular heart surgery. Additionally most of our adultpopulation has no health or life insurance. These patients either find it hard to get a job due totheir pre-existent illness history or they are systematically rejected when the scar of aprevious sternotomy is detected in the physical exam.The creation of a multidisciplinary team should include: 1) pediatric and adultcardiologists trained in adult congenital heart disease; 2) experts in the different imagingmodalities to deal with the whole spectrum of congenital cardiac lesions and the surgicaltechniques as well, v.g.: transesophageal and three dimensional echocardiography, cardiacmagnetic resonance and multislice computed tomography; 3) an interventional cardiologisttrained in all the procedures inherent to this specialty; 4) a cardiovascular surgeon expert in

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complex congenital heart surgery and reoperations and an adult surgeon to attend to thepotential associated coronary artery disease; 5) experts in cardiovascular postoperative caretrained both to treat children and adults; 6) electrophysiologists familiarized with theanatomical and surgical variants of congenital defects; 7) gynecologists capable to cope withhigh risk pregnancy cases, etc. This specialized center would treat a considerable number ofadults with congenital heart disease with good surgical results. The larger the amount of adultpatients the shorter the learning curve. It also would be the ideal institution to train bothpediatric and adult cardiologists in adult congenital heart medicine.

AbstractChildren with congenital heart disease require adequate clinical support. Intensivecare units (neonatal and cardiovascular) and pediatric emergency departments have avital role in the care of these patients. This chapter presents the key aspects for propermanagement of these children: early diagnosis, timely treatment, clinical support andprevention and treatment of complications.

1. IntroductionCHD are not preventable diseases at this time. The only way to currently improve theprognosis lies in early diagnosis and this is essential to the successful treatment of thesepatients. One third of all children with CHD will suffer a serious critical illness during thefirst year of life and will either die or receive surgical intervention [1, 2]. Surgical delayimpairs the patient's clinical condition and is associated with a high morbidity and mortality.The more common scenarios include children with large ventricular septal defects, heartfailure and respiratory infections while waiting for surgical repair.

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The success of surgery in infants with CHD has led to an increasing number of patientswho will require monitoring for the development of residual complications. In some cases,reoperation is required. If the CHD is not repaired, it may result in progressive andirreversible damage of the heart (e.g. myocardial hyperplasia, coronary angiogenesis), lungswith abnormal vascular bed/alveolar development and abnormal neurocognitive development.

2. The Emergency Physician and Congenital Heart

Diseases. When Should CHD beClinically Suspected?The emergency department is a good setting to identify children with undiagnosed CHD;therefore it is important for emergency physicians to have knowledge of the different clinicalforms of CHD and their presentations. CHDs include a very heterogeneous group of lesionswith a diverse pathophysiology and complications; however, they are represented by only asmall number of signs and symptoms. The main forms of clinical presentations of CHD andtheir complications are as follows:

CyanosisCyanosis is the appearance of a blue coloration of the skin or mucous membranes and isone of the most important physical signs of CHD and its complications. Because cyanosisdepends on the absolute concentration of hemoglobin, it is more apparent in children with ahigh hematocrit and less so when they are anemic. If hemoglobin levels are normal, cyanosiscan be detected when blood saturation values drop below 85%. There are two forms ofcyanosis: central and peripheral. Central cyanosis is usually seen on the tongue and lips andoccurs as a consequence of low arterial saturation due to heart, lung or neurological diseases.Peripheral cyanosis, on the other hand, results from a decrease in local blood circulation butwith normal blood arterial saturation. This is frequently seen on the arms and legs in patientswith heart failure, shock, diseases of blood circulation (thrombosis/embolism) and exposureto cold temperatures. All causes of central cyanosis can lead to peripheral cyanosis, but not allcauses of peripheral cyanosis can lead to central cyanosis.In patients with suspected cyanosis, the first step is to identify the patients baselinesaturation at room air. Emergency physicians should ask brief questions looking for a history(e.g. neonatal asphyxia, meconium aspiration or low Apgar score) that predisposes the patientto getting permanent pulmonary hypertension. A chest radiograph (CXR)is a good diagnostictool that can be used to show the shape and size of the heart, estimate the flow of pulmonarycirculation and detect lung pathology.The hyperoxiatest is another simple and useful test for diagnosing the cause of cyanosis.It is performed by initially giving 100% oxygen for 10 minutes before measuring oxygensaturation with either pulse oximetry or blood gases. If the oxygen saturation does not changeor the arterial oxygen pressure does not rise above 70 mmHg, it is very likely that the patienthas cyanotic congenital heart disease.

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However, if the oxygen saturation rises above 150 mmHg, it is very unlikely to becyanotic congenital heart disease because these patients rarely have PaO2 values greater than150 mmHg. When the PaO2 is between 70 and 150 mmHg, cyanotic CHD can neither beconfirmed nor excluded and additional studies must be performed. In summary, a lack ofresponse to the hyperoxia test supports the suspicion of cyanotic CHD and an urgentechocardiogram should be performed.

Heart FailureHeart failure results from a multisystem imbalance that arises, in most cases, when theheart is no longer able to fill or to eject the blood delivered to it by the venous system.Contrary to what happens in adults where the etiology is usually ischemic, heart failure incongenital heart disease is commonly caused by volume and/or pressure overload. Anamnesisshould be directed to identify feeding difficulties, sweating, poor weight gain, stridor, chestpain or syncope. Tachycardia, tachypnea, breathlessness, presence of a third heart sound, finerales at the lung bases, hepatomegaly, soft tissue edema, oliguria, heart murmurs, distendedneck veins and absent or weak femoral pulses are frequent signs and symptoms of heartfailure in children. Some children with obstructive left heart diseases such as coarctation ofthe aorta, interrupted aortic archand hypoplastic left heart syndrome may present withcardiogenic shock to the emergency department. Often, this latter situation is incorrectlyinitially interpreted and treated as septic shock.

Heart MurmursCongenital heart disease should be considered when a heart murmur is accompanied withother signs and symptoms such as cyanosis or heart failure. Murmurs should be analyzedaccording to their different characteristics: timing, location, radiation, intensity, pitch andquality. Intense, diastolic and continuous murmurs are considered pathological as are all thoseaccompanied with an abnormal physical examination.

3. Value of Additional Testing for CHD in the

Emergency DepartmentIn the face of suspected CHD, the emergency physician should order a CXR,electrocardiogram and echocardiogram. ACXR provides information about the size and theshape of the heart as well as the status of the lungs. Some CHDs may have classic findingssuch as the boot shaped heart seen in Tetralogy of Fallot and may also show signs ofpulmonary hypoflow or hyperflow. Additionally, pediatric emergency physicians shouldalways calculate the cardiothoracic index (a clinical method of expressing the size of theheart). A value greater than 50% suggests cardiomegaly. However, cardiothoracic indexinterpretation in young children can be difficult due to the presence of the thymus. Anelectrocardiogram (ECG) is useful for determining chamber hypertrophy, arrhythmias and

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repolarization disorders. Emergency physicians must be aware that the interpretation of

pediatric ECGs and what is considered a normal ECG in a child is very different from that ofan adult.An echocardiogram is a very important tool that provides information about cardiacstructure and function. However, because a pediatric echocardiogram is a unique andspecialized, a physician with experience with performance and interpretation shouldperform it.Chamber hypertrophy diagnosis criteria are as follows:RIGHT ATRIAL HYPERTROPHYLEFT ATRIAL HYPERTROPHYRIGHT VENTRICULARHYPERTROPHY

LEFT VENTRICULARHYPERTROPHY

Peaked P waves (P pulmonale)

Biphasic waves of lengths greater than 0.08 in infantsand 0.10 in childrenPositive T waves in right pre-cordial leads(from V4 to V2)QRS right axis deviation greater than 120 degreesDominant qR and R in right leads (V3 and aVR)Deep S wave in left sided leadsST segment depression and inverted T waves in leftsided leadsPeaked R wave in V6Deep S wave in right sided leadsDeep Q wave in V5 and V6

4. Clinical Presentation and Preoperative

Management of CHD in NeonatesCHD with Left Sided Obstructive Lesions and Ductal-Dependent SystemicBlood FlowNeonates with CHD with left-sided obstructive lesions have symptoms stemming fromclosure of the ductus arteriosus. As a result, this leads to progressive metabolic acidosis andeither congestive heart failure, cardiovascular collapse or shock. These left-right shunt lesionscan be stabilized by keeping the ductus arteriosus open. This improves the cardiac output byallowing the right ventricle to support systemic blood flow. If this type of CHD is clinicallysuspected, prostaglandin (PGE1) infusion should be promptly started and treatment shouldproceed even without echocardiography confirmation [3]. This is the essential managementfor survival because it maintains ductal patency and balances the flow between pulmonaryand systemic circulations. Peripheral organs can be affected by the resultant decrease inperfusion. Acute renal failure, necrotizing enterocolitis and intraventricular hemorrhages arecommon squeals of these lesions, especially if not managed properly. Clinical symptomsincludes sub-acute onset of fussiness, poor feeding, pallor, respiratory distress and oliguria. Ifthese symptoms are present, sepsis should be strongly considered and low threshold must bemaintained for obtaining cultures and treating empirically with antibiotics.

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To prevent excessive pulmonary blood flow, the pulmonary vascular resistance can bemanipulated by adjusting the ventilation. In general, the ventilator setting should be managedas follows: titrate the FIO2 to keep systemic arterial saturation between 75- 80 %, allowenough tidal volume to obtain good chest expansion and maintain the peak inspiratorypressure> 25 cm H20 and positive end-expiratory pressure at 4-6 cm H2O. In addition, higharterial saturation and respiratory alkalosis should be avoided and the hematocrit should bekept close to 40%. Endovenous inotropics should be considered if there is clinical suspicionof excessive pulmonary blood flow.Left-sided obstructive CHD types include coarctation of the aorta, interrupted aortic arch,critical aortic stenosis and hypoplastic left heart syndrome.Coarctation of the Aorta in the neonate results from the acute onset obstruction ofsystemic blood flow leading to left ventricular pressure overload and failure with subsequentelevation of left atrial pressure and pulmonary edema. The severity of this lesion depends onthe degree of the coarctation, the patency of the ductus arteriosus and the presence ofassociated intracardiac lesions (e.g. ventricular septal defects). Coarctation may also beassociated with other complex CHDs like truncus arteriosus, double outlet right ventricle,single ventricle lesions and Shone's complex [4].Interrupted Aortic Archmay be associated with ventricular septal defects, bicuspid aorticvalve, truncus arteriosus, transposition of the great arteries, double outlet right ventricle andsingle ventricle complexes. Calcium levels should be closely monitored due to the frequentassociation with 22q11 chromosome deletion.Critical Aortic Stenosisin neonates leads to pressure overload in the left ventricle,elevated end-diastolic pressure, elevated left atrial pressure and pulmonary edema. The leftventricle is generally dilated with poor contractility. Inadequate coronary blood flow resultsfrom tachycardia and increased left ventricular end-diastolic pressure [5].

CHD with Right-Sided Obstructive Lesions and Ductal-Dependent

Pulmonary Blood FlowRight-sided obstructive lesions usually present with central cyanosis, and pulmonaryblood flow is dependent on the L-R shunt through the ductus arteriosus. The degree ofcyanosis hinges on the patency of the ductus and may worsen with ductal constriction. Thehyperoxia test with arterial blood gas measurement helps differentiate between a respiratoryor cardiac origin. Management includes prompt infusion of PGE1 to keep the ductusarteriosus open until a Blalock-Taussig shunt can be surgically placed. In addition, ventilationmanagement is always a primary concern in order to decrease peripheral oxygenconsumption. Optimizing intravascular volume and maintaining the hematocrit around 40%improves oxygen delivery. Hyperventilation and correction of metabolic acidosis, togetherwith pharmacological sedation and neuromuscular blockade, may help decrease peripheralvascular resistance. CHD with right-sided obstructive lesions and ductal-dependentpulmonary blood flow includes Tetralogy of Fallot with pulmonary stenosis, Tetralogy ofFallot with pulmonary atresia, Ebstein's anomaly (without atresia of either the pulmonaryatresia or tricuspid valve and tricuspid atresia), critical pulmonary stenosis and pulmonaryatresia with intact ventricular septum. Since some of the lesions associated with tricuspidvalve atresia and pulmonary atresia with intact ventricular septum and Tetralogy of Fallot

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with pulmonary atresia also have single ventricle physiology, their treatments are discussed inother sections.

Transposition of the Great Arteries

In Transposition of the great arteries, the systemic and pulmonary circulations are inparallel (Graph 1: Parallel circulations). In this circumstance, most of the output of eachventricle is re-circulated back to the respective ventricle. To survive, certain anatomic sitesmust exist to allow for intercirculatory mixing of the pulmonary and systemic blood.Intracardiac:

patent foramen ovale

atrial septal defectventricular septal defect

Extracardiac:

patent ductus arteriosus or

bronchopulmonary collateral circulation

In patients with adequate interatrial or interventricular defects size, the level of arterialoxygen saturation is influenced primarily by the pulmonary-to-systemic blood flow ratio. Ahigh pulmonary blood flow results in relatively high arterial oxygen saturation as long as theventricles can adequately maintain the high output state. In situations with decreasedpulmonary blood flow, an elevated pulmonary vascular resistance should be considered if thearterial oxygen saturation decreases despite adequately sized anatomic shunt sites [6, 7].LA

RA

LV PA LUNG CIRCULATION

RV AO SYSTEMIC CIRCULATION

Graph 1. Parallel circulations.

In transposition of the great arteries with an intact ventricular septum, there is inadequatemixing at the foramen ovale level which results in severe secondary hypoxemia anddeficiency of oxygen supply to the tissues. An excessive right and left ventricular workload isalso present. If the ductus arteriosus is closing, profound hypoxemia with pO2 < 20 mm Hgcan be seen. Only a relatively small proportion of blood is exchanged by mixing between thetwo circulations, and as a result, only a small proportion of the effective circulation reachesthe appropriate vascular bed.

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To stabilize the patient, PGE1 must be started and emergent balloon atrial septostomymust be performed to enlarge the foramen ovale. In addition, hyperventilation and increasedFIO2 may help to increase pulmonary blood flow. Although there is no CHD for which PGE1is contraindicated, in cases of transposition of the great arteries with a restrictive atrialseptum, cyanosis may be exacerbated by PGE1 infusion due pulmonary edema until atrialseptostomy is performed [8].Congested lungs are also observed in obstructed total anomalouspulmonary venous return and emergent surgery is required to treat both of these conditions.

Single Ventricle Lesions

In this group of lesions, there is complete mixing of the systemic and venous return at theventricular or atrial level. Therefore, the ventricular output must be divided between the twocompeting parallel circuits: the pulmonary and systemic arterial circulations. In singleventricle lesions, the pulmonary artery and aortic oxygen saturations are equal, and theventricular output is the sum of the pulmonary blood flow (Qp) and the systemic blood flow(Qs). The proportion of the ventricular output that is directed to the pulmonary or systemicvascular bed depends on the amount of resistance to the flow into these circuits. The degreeof obstruction to pulmonary outflow depends on the presence of the following conditions:pulmonary stenosis, pulmonary vascular resistance, pulmonary venous obstruction and leftatrial pressure (obstruction to outflow through the left atrioventricular valve and atrialseptum). On the other hand, the following conditions and severity determine the degree ofobstruction to systemic outflow: the degree of subaortic or aortic valve stenosis, coarctationof the aorta, systemic vascular resistance and the size of the ductus arteriosus.In some cases there is no outflow obstruction to the pulmonary and systemic circuits;therefore, before surgical procedures, ventilator and pharmacologic maneuvers are needed.The objective is to balance the ventricular output between the parallel circulations with thegoal of having the systemic and pulmonary vascular beds achieve a Qp/Qs ~ 1. Thesemaneuvers provide adequate systemic blood flow and oxygen delivery to prevent acidosis anddecreases single ventricle volume overload.PV Sat (95-100%) PA 02Sat (75-80%) 20-------------------------------------------------- = ------- Qp/Qs: ~ 1A02 Sat (75- 80%)- MV O2Sat (55- 60%) 20

Patients with single-ventricle physiology and high arterial oxygen saturations (>90%):aregenerally seen in those where the combined ventricular output is redirected into thepulmonary vascular circuit. This causes a reduction in the systemic flow, which results ininadequate tissue perfusion, metabolic acidosis, low cardiac output and shock.Once establishment of a patent ductus arteriosus is confirmed, maneuvers to minimizesystemic vascular resistance and maximize pulmonary vascular resistance should be used.One method to increase pulmonary vascular resistance is to add supplemental inspiredgases, nitrogen [10, 11] or carbon dioxide [12].This mechanism is likely due to the inductionof alveolar hypoxia [13]. Other maneuvers include mechanical ventilation withpharmacological sedation and paralysis to allow permissive hypoventilation (elevate thePCO2to a goal of 40 to 50 mmHg) [14], correct metabolic acidemia, avoid excessiveinotropic support (doses which favor alpha receptors), after load reduction with sodiumnitroprusside and maintain the hematocrit greater than 40% to 45% (increased viscosity mayalso help to elevate pulmonary vascular resistance).If a patient with unstable physiology requires intubation and pharmacological sedation tomaintain adequate systemic blood flow, they should undergo urgent surgical management toachieve a more favorable physiology. This is the typical presentation of hypoplastic left heartsyndrome, a left-sided obstructive lesion with ductal-dependent systemic blood flow.

Prostaglandin AdministrationThe initial intravenous dose of PGE1 is 0.05 mcg/kg/min. If there is no improvement, thedose should be increased to 0.1 mcg/ kg/ min. After the infants condition has stabilized, theusual maintenance dose of PGE1 is 0.025 mcg/kg/min. Apnea, bradycardia, hypotension,fluid-electrolyte imbalances, irritability, fever and cutaneous flushing are all potentialcomplicating side effects of PGE1.Therefore, management of the airway is essential along with excluding the possibility ofsepsis.

Management of Cardiac Emergencies in Children with Congenital Heart Disease

intubation is performed, it is essential that the prostaglandin administration continue at thesame dose or higher. Long-term use is associated with cortical hyperostosis, but it is a sideeffect that does not seem to be dose related. Monitoring in an intensive care unit is required.

Clinical Presentations and Management of Complications of CHD

in ChildrenAttacks of HypoxemiaEmergency physicians who work in emergency departments should have extensiveknowledge of the management of attacks of hypoxemia. Children with CHD in whichpulmonary blood flow is reduced may suffer from these episodes. Examples of these includeTetralogy of Fallot, tricuspid atresia and pulmonary atresia with an intact ventricular septum.Hypoxemic attacks are surge episodes of intense cyanosis due to desaturation; thesubsequent irritability and dyspnea results from an acute decrease in pulmonary blood flow.These may be of varying intensity and duration, and the most serious cases cause impairedconsciousness, seizures and death. Although attacks of hypoxemia may happen at any age, theincidence seems to increase after 4 to 6 months of age and is one of several reasons forneeding complete surgical repair before this age. Fortunately, the incidence of attacks ofhypoxemia has decreased because many patients with cyanotic CHD undergo early surgicalcorrection.PathophysiologyUntil now, the exact nature of these events has been unknown. However, variousmechanisms (or some combination thereof) have been described:

Infundibulum spasm: Cyanotic attacks happen as a result of the spasmodic

contraction of part of the right ventricular outflow tract called the Infundibulum.However, this theory fails to explain why children with pulmonary atresia alsoexperience attacks of hypoxemia. Children with this condition have an undevelopedsubpulmonic infundibulum.Changes in systemic vascular resistance: Sudden changes in systemic vascularresistance can increase the intensity of the intracardiac right-to-left shunt.Sudden changes in venous return to the heart can also affect the right-to-left shunt.Abrupt changes in heart rateAlterations in sensitivity of the respiratory center

Different factors that cause patient agitation can trigger attacks of hypoxemia. Significantstressful situations, crying, invasive medical procedures and conditions such as dehydrationhave all been described. Because attacks of hypoxemia are more frequent in the morning,shortly after waking, it is thought that the sudden changes in pCO2 that occur after a lengthysleep may explain the hypercyanosis crisis.Infundibulum spasm and/or other mechanisms such as tachycardia increase the right-toleft shunt and cause hypoxemia and acidosis. To compensate, this creates a vicious feedback

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loop cycle wherein the patient begins to hyperventilate in order to increase the venous returnand decrease the systemic vascular resistance, which then exacerbates the right-to-left shunt.A progressive cycle of decreased pulmonary blood flow, increased cyanosis and worseningmetabolic acidosis develops from the imbalance between pulmonary and systemiccirculations.Clinical FindingsAt presentation to the emergency department, these children usually have a previousdiagnosis of their CHD and parents have already witnessed crises of varying intensities.Often, they tend to state that the events have been getting more severe and/or more frequent.These patients usually have different degrees of cyanosis and can adopt positional maneuverssuch as squatting to improve their condition. A squatting position is often seen in childrenwith this condition after exerting near maximal effort. The mechanism is due to compressionof the femoral arteries, which results in an increased peripheral resistance and a decreasedright-to-left shunt. In some patients, they may present with little or no evidence of cyanosisbefore the onset of the attack.However, in the majority of cases, the cyanosis is quite obvious. Their clinical signs mayrange from simple crying and fussiness to a more extreme neurological status such as lethargyand even coma. Tachypnea is always seen with these attacks, however the differentialdiagnosis for tachypnea is long and other medical problems should be considered as well.In children with Tetralogy of Fallot, the intensity and length of the systolic ejectionmurmur is closely related to the degree of infundibulum obstruction. During the spell, apreviously heard heart murmur may be absent or decreased because pulmonary blood flowthrough the stenotic right ventricular outflow tract is reduced. There is usually only a singlesecond heart sound due to the absence of the pulmonary component.Attacks of hypoxemia can last from a few minutes to several hours and can be fatal. Shortepisodes typically end with the patient becoming weak and sleepy, however more severecrises can cause seizures, hemiparesis, brain ischemia and even coma.ManagementThese patients require immediate attention in the emergency department. Appropriatepositioning of the head, administration of oxygen and morphine are the first measures to takein order to reduce or terminate the attack.Treatment is greatly based on increasing the systemic vascular resistance to decrease theright to left shunt. It is very important to keep the child calm and close to his/her parents andto avoid any painful or invasive procedures that could worsen the crisis. Sometimes it ishelpful to reduce ambient light intensity and parents should be asked to keep the child in aknee-chest position in order to increase systemic vascular resistance.Oxygen should be administered to improve saturation and raise PaO2 levels. Oxygen isadministered despite the fact that this measure may prove unsuccessful due to the reduction ofpulmonary blood flow during the spell.Even though its exact mechanism of action is unknown, administration of large doses(0.1 to 0.2 mg/kg) of subcutaneous morphine is usually used to treat the attack. In theory,morphine depresses the respiratory drive, which interferes with the hyperpnea cycle and leadsto vasomotor changes. It may also be useful to administer a sedative agent likeintramuscular/intranasal midazolam (0.5 mg/kg).

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Ketamine may also be used to decrease agitation and increase systemic vascularresistance. Sometimes the required sedation causes respiratory depression and the patient mayneed to be intubated. Nevertheless, mechanical ventilation does not improve oxygenationbecause the problem is restriction of pulmonary blood flow.If the crisis continues, additional measures are needed.

Sodium bicarbonate may be administered intravenously at a dose of 2-3mEq/kg.

oxygenation may occasionally be needed. If patients require mechanical ventilation, it isrecommended to perform rapid sequence intubation with drugs such as ketamine because itincreases systemic blood pressure. Avoid drugs that cause hypotension such asbenzodiazepines.Attacks of hypoxemia should not be confused with heart failure because inotropics,diuretics and vasodilators are contraindicated in these hypoxic events. If cardiac arrhythmiasoccur during management, they should be promptly treated. Even though relieved withtreatment, hypoxemiausually indicates that surgery will be required for definitive treatment.To avoid future crises, physicians should warn parents to avoid triggering factors such aspain, hunger and stress as well as processes that cause vasodilatation such as fever and hotwater [15].

Heart Failure: L-R Shunt Lesions

A L-R shunt cardiac lesion is an abnormal connection between the left and right side ofthe heart and includes atrial septal defects, ventricle septal defects, atrioventricular septaldefects and patent ductus arteriosus. Of these, the most common types are ventricle septaldefects, atrioventricular septal defects and patent ductus arteriosus and the definitivetreatment is corrective surgery. The flow across the cardiac shunt depends on the size of thedefect and the pressure difference between the two chambers on either side of the shunt.However the pressure difference is the most important factor in determining the amount offlow across the shunt. Blood will always flow from the high pressure chamber to the lowpressure chamber. Therefore, in a normal heart (in the presence of a shunt), flow will be fromleft to right. When larger pressure-difference between the chambers, then more blood that willbe shunted across the defect. . In newborns, the pulmonary vascular resistance and the right

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heart pressures are high resulting in a low-pressure gradient between the left and right sides ofthe heart and minimal flow across the defect. In these lesions, the myocardial contractility iswell preserved, but cardiac failure occurs because the systemic circulation is less perfusedwhile pulmonary circulation is overflowing with high Qp: Qs ratios greater than 1.5:1. Theselarge shunts lesion are at risk for congestive cardiac failure with pulmonary hypertension dueto the increased pulmonary blood flow and over circulation.L-R shunt lesions symptoms and signs include murmurs as well as those consistent withcongestive heart failure. Murmurs heard in shunt lesions are often generated by the turbulentblood flow across a valve. They are present when a pressure gradient develops after theneonatal pulmonary vascular resistance falls between 4- 6 weeks of age. An ASD murmur iscaused by the turbulent flow over the pulmonary valve as a result of a relative pulmonarystenosis (PS). On the other hand, a large ventricular septal defect will lead to excess bloodreturning to the left atrium and the consequent turbulent flow through the mitral valve resultsin a relative mitral stenosis. This is heard as a mid-diastolic rumble. Signs of congestive heartfailure include tachycardia, cardiomegaly, congested lungs sounds, hepatomegaly andperipheral edema.Tachypnea, dyspnea and wheezing are present due to interstitial pulmonary edema with adecrease in lung compliance and increase in airway resistance. This situation causesatelectasis, ventilation/ perfusion (V/Q) mismatching, pulmonary hypertension and increasesthe work of breathing (recruitment of intercostal and subcostal muscles). There is a high riskfor failure to thrive due to the high-energy cost of breathing. Management in stable patientsinvolves diuretics (furosemide), digoxin and hypercaloric feedings, however surgery isultimately required for definitive treatment.In decompensated patients with congested lungs, intravenous diuretics should beadministrated often, but oxygen therapy should be used with prudence because it will causevasodilatation of the pulmonary circulation, which may worsen the increased pulmonaryblood flow. It is recommended to maintain oxygen saturation levels at 85- 90%. If respiratorydistress is present with an increased work of breathing, it may help to start with non-invasivepositive pressure ventilation with a low FiO2; if the patient worsens, however, more invasivemechanical ventilation is needed. The positive pressure helps to reduce after load, alveolaredema, atelectasis and the metabolic demand. If additional inotropic support is necessary,catecholamines may be used; intravenous dobutamine (more of an inotropic than anchronotrope) infusion can also be safely administered in the emergency department. In casesof severe shock, dopamine or epinephrine may be used but preferably in an ICU setting.Lastly, it is important to optimize the hematocrit to nearly 40% and start nasogastric feedswhen appropriate to ensure adequate nutritional support [16].

5. General Management of Critically Ill Children

with Congenital Heart Disease in theEmergency DepartmentGeneral interventions in the emergency department must be rapidly performed in patientswith known (repaired or unrepaired) or suspected CHD. Initial management should includethe following steps:

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1. Address the ABCs (Checking the airway, breathing and circulation)

2. Administer oxygen in order to achieve their baseline level of saturation (this levelcan usually be provided by the parents)3. Secure vascular accessCaution should be taken in children with Tetralogy of Fallot since pain or fear canworsen their hypoxemic attacks. If decompensated shock is present and vascular accesscannot be obtained, an intraosseous line must be strongly considered.4. Prudent initial fluid administrationStart with 5-10 mL/kg boluses unless there is concern for dehydration or hypovolemia. Ifone of these conditions is present, use 10-20 mL/kg boluses instead.5. Continuous monitoring of blood pressure, heart rate and rhythm and pulse oximetry6. Echocardiogram should be performed urgently7. Obtain complementary studies such as CXR, ECG, blood gas, hematocrit, serumelectrolytes and lactate8. Cardiology and pediatric intensive care unit consultationA rapid assessment should be performed to categorize the child with unrepaired orrepaired CHD. After addressing the ABCs, close observation of the general appearance andcolor may provide useful details about the degree and distribution of the cyanosis. Atbaseline, these patients are often pale or cyanotic and have an increased work of breathing.Caregivers information may help guide the physicians assessment. Oxygen saturation in achild with corrected congenital heart disease may be low in contrast with their baseline level.Supplemental oxygen administration should be titrated to meet the patients baseline, butonce this level has been reached, additional oxygen support may be harmful.Emergency physicians should also know how to check pre-ductal and post-ductal oxygensaturations (on the right hand and left foot simultaneously). A difference of 10% or greaterbetween the two suggests cardiac disease [17]. Often, a quick assessment of the patient canprovide important details about their hydration and respiratory status. At this point parentsinformation must be considered, as they will likely know their childs baseline breathingcondition and other important details.Assessment of circulation must include the patients color, central and peripheral pulses(radial and femoral pulses should be palpated and compared) and blood pressure on all fourextremities. If a difference of greater than 20 mm Hg exists between the upper and lowerlimbs, coarctation of the aorta should be considered. Signs of congestive heart failure such ashepatomegaly, gallop rhythm and jugular venous distention must also be assessed.When assessing for murmurs, physicians should ask themselves the following questions:If there is a murmur:1. Does the patient have a baseline murmur?2. Is this murmur new?If there is not a murmur:

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3. Did the child previously have one?

Neonatal stabilization and transport:

Most neonates with congenital heart diseases need stabilization in an intensive care unitwith highly trained staff. The following steps must be taken into account for stabilization:1. Maintain the patency of the ductus arteriosus with prostaglandins if you suspect aductal-dependent lesion. The availability of these drugs should be ensured at allemergency departments.2. Provide proper ventilation and oxygenation; mechanical ventilation is required incases of respiratory distress or severe cyanosis. It is advisable to keep oxygensaturation at near 80% especially in patients with heart failure. Excessive oxygensaturation can decrease vascular resistance due to pulmonary vasodilatation and canworsen the severity of symptoms.3. Secure reliable vascular access. The umbilical vein is often useful in this case, whichis typically accessible until one week of age.4. Proper monitoring should include continuous oxygen saturation, measurement oftemperature, blood pressure (ideally with an arterial catheter) and laboratory tests(calcium, blood sugar level and blood count and serum electrolytes).5. Use inotropic agents with caution to prevent myocardial injury. Digitalis drugs arenot recommended.6. Fluid expansion and bicarbonate should be used in the presence of shock.7. Use parenteral nutrition until shock is treated to avoid necrotizing enterocolitis.After stabilization, neonates must be transferred for their definitive care and meticulous,thorough communication with the receiving center is necessary.

6. Management of Systemic Complications

of Congenital Heart Diseases in theEmergency DepartmentEmergency physicians should be aware of systemic complications that may occur inpatients with CHD in order to appropriately manage these children.

Cardiac ComplicationsCardiac complications such as low output syndrome, postoperative heart failure andarrhythmias are usually seen in pediatric intensive care units. However, emergencydepartment physicians should be familiar with these and be particularly attentive in childrenwho have recently undergone surgery.Low output syndrome is the most common postoperative complication. Patients maypresent with tachycardia, weak pulses, delayed capillary refill, peripheral vasoconstrictionand oliguria. Invasive monitoring will show decreased central venous pressure, tachycardia,normal or low blood pressure and elevated arterial resistance. Laboratory findings typically

Management of Cardiac Emergencies in Children with Congenital Heart Disease

Renal ComplicationsIn patients with CHD, it is important to evaluate the patient for renal complications (e. g.renal failure) in the immediate post-operative period and to obtain the most recent BUN andcreatinine blood values.CHD is the most common cause of acute renal failure in infants [18]. The main causesare:

Vascular stress of surgery (causes a reduction in renal blood flow and glomerularfiltration rate, vasopressin release and shift of blood from the cortex to the medulla)Low cardiac output or cardiac arrestMedications used to improve cardiac function (inotropics medications,phosphodiesterase inhibitors)Mechanical circulatory support (extracorporeal circulation)Hypothermia (produces a decrease in renal blood flow)

The Multi-Societal Database Committee for Pediatric and Congenital Heart Diseasedefines acute renal dysfunction as new onset oliguria with sustained urine output < 0.5ml/kg/h for 24 hours and/or a rise in creatinine > 1.5 times the upper limit of normal adjustedfor age (or twice the most recent preoperative values) and eventual recovery of renal functionwithout needing dialysis [19]. On the other hand, acute renal failure is defined by the samenumerical parameters but without recovery and with eventual need for dialysis orhemofiltration. Renal dysfunction is relatively frequent and transitory in the immediatepostoperative period and is managed in intensive care units [20]. Clinical managementincludes adequate hemodynamic control, proper fluid balance and diuretics; dialysis isperformed only if necessary.

Hematological ComplicationsThere is a long list of hematological complications for children who have undergonesurgery for CHD. The most frequent disorders are anaphylactic reactions to blood products orantifibrinolytic drugs, cold agglutinin reactions, prothrombotic and/or hemorrhagic reactionsand sickle cell crises [21].The use of extracorporeal circulation or cardiopulmonary bypass and heparin increasesthe risk of bleeding in patients who have recently undergone surgery. Pediatric intensive care

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units must monitor the coagulation status because oftentimes these patients needadministration of flesh-frozen plasma, platelets and/or packed red blood cells. Coagulationdisorders are more common in children younger than 6 months since they often have arelative decreasing coagulation factors, thrombocytopenia and increased bleeding andactivated partial thromboplastin times.After some procedures, such as the Glenn or Fontan procedures, patients will need tocontinue with anticoagulation therapy. Emergency physicians should always ask about theseprocedures and the use of anticoagulation drugs like heparin, warfarin or aspirin becausechildren may present with signs and symptoms of intracranial hypertension secondary tointracranial hemorrhage. The patient must be closely observed for neurological signs, arterialhypertension, vomiting, blurred vision, anisocoria and even a coma state.

Infectious ComplicationsChildren who have undergone surgery for CHD may have complications such us woundinfection, mediastinitis, pneumonia, endocarditis or sepsis. If any of these infectiouscomplications are present, patients must be admitted for further evaluation and immediatetherapy. Sometimes children may present with fever without a known source after surgery ofCHD. In this case, if surgery was recent, hospital admission is advisable and a meticulousinvestigation for the source of infection initiated. Patients with wound infections may havefever, chest pain and obvious signs of swollen, with or without drainage. The emergencyphysician must take into account the type of procedure, predisposing factors (conditionswhich suppress immunity) and the patients general appearance. The pathogen involved withspecific infections will depend on the epidemiological characteristics of each institution. In allcases it is necessary to obtain blood and wound cultures. The type of antibiotic to use variesand is specific to each particular case.The true incidence of pediatric endocarditis is unknown. In Argentina, at HospitalNacional de Pediatra Juan P. Garrahan, the incidence is approximately 4.9/10,000admissions/year [22].Among patients with underlying heart conditions, CHD represents the highest percentageof children presenting with infectious endocarditis. CHD is a predisposing factor forendocarditis and, in adults, the incidence increased from 4.2% in 1992 to 9.5% in 2002.CHD that could most easily be complicated by the development of endocarditis areventricular septal defects, patent ductusarteriosus, abnormalities of the aortic valve andTetralogy of Fallot. Cyanotic conditions and partially repaired shunts are at highest risk.Although complete repair of ventricular/atrial septal defects and patent ductus arteriosusalmost completely removes the risk of endocarditis six months after the procedure,21%-50%of children with infectious endocarditis have had a history of cardiovascular surgery (with orwithout vascular implants, patches or prosthetic valves) [22]. In summary, the clinicalpresentation of endocarditis in children is often non-specific, and emergency physiciansshould always keep this condition in mind if the patient has underlying CHD.Signs and symptoms of endocarditisFeverHepatomegaly

%87%62%

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Extracted and modified from Paganini Hugo R. Pediatric Infectious Diseases. FirstEdition, Ed 2007 Scientific American, Cap 72. P. 483.The mortality rate in children with CHD is approximately 12.8%.The recommended diagnostics tests include blood cultures, urinalysis and culture,complete blood count, BUN and creatinine levels, CXR, C-reactive protein, erythrocytesedimentation rate, electrocardiogram and echocardiogram. However, laboratory findings arenon-specific and results such as anemia, leukocytosis, hemolysis, elevated C-reactive proteinand erythrocyte sedimentation rate, hematuria and proteinuria may or may not be present.Blood cultures are the most important tests for diagnosis. They must be obtained in theemergency department at the time of presentation. It is advisable to obtain adequate bloodvolume: 1-3 ml for infants and 5-7 ml for children. The decision whether to use antibiotictherapy in the emergency department will depend on the patients clinical condition. It is notusually necessary to start antibiotic treatment in the emergency department unless the patientappears seriously ill.After recent surgery, children with high fever and signs of wound infection may alsopresent with acute mediastinitis. These patients may have pain or instability of the sternum;occasionally, mediastinitis may present as septic shock without localizing signs. After thepatient is stabilized and antibiotic treatment initiated, a computed tomography of the chestmay help clarify the diagnosis.

Pulmonary ComplicationsPulmonary complications of CHD such as primary or secondary respiratory arrest orventilator-associated pneumonias are sometimes seen in the pediatric intensive care unit postoperatively. Other pulmonary complications include atelectasis, pneumothorax,bronchospasm, pleural effusion and chylothorax. Signs and symptoms such as dyspnea, fever,hypoventilation, hypoxemia and respiratory acidosis will suggest these conditions. In patientswith symptoms or signs of pulmonary complications, a CXR, arterial blood gases, bloodcultures and complete blood counts should be obtained. Antibiotics, pleural effusion drainageand parenteral nutrition may be part of the treatment, depending on the situation. In cases ofrespiratory distress and respiratory acidosis, mechanical ventilation must be considered early,before further descompensation.

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Guillermo A. Kohn Loncarica and Guillermo E. Moreno

Neurological ComplicationsNeurological complications of CHD are uncommon, however surgeries that requirecardiopulmonary bypass, deep hypothermia and patients who have intracardiac shunts carry ahigher risk. The main complications are ischemic or hemorrhagic stroke and seizures. In theemergency department, a magnetic resonance imaging or computed tomography should beordered if stroke is suspected.

ArrhythmiasIn the presence of an arrhythmia in a patient with CHD, the ABCs must be rapidlyaddressed, venous access secured, and immediate ECG performed. The key features of ECGanalysis in this situation are to determine whether a sinus rhythm is present, with regular,narrow QRS complexes, with each complex preceded by a P wave and each complex uprightin lead I and aVF. Brady arrhythmias or congenital complete heart block may be associatedwith CHDs (in particular, with corrected transposition of the great arteries, Ebsteinsmalformation, and other similar lesions) or related to a surgical procedure, but may also occurin a structurally normal heart. A diagnosis of complete heart block with a low cardiac outputneeds emergent medical treatment with isoproterenol, and urgent insertion of a pacemakermay be necessary.

ConclusionCHD are not preventable diseases and require adequate clinical support. The only way tocurrently improve the prognosis lies in early diagnosis and this is essential to the successfultreatment of these patients. Pediatric intensive care units and emergency departments have avital role in the care of these patients.